Disubstituted xanthone carboxylic acid compounds

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, novel disubstituted xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions and intermediates therein are also disclosed. 5-Methylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid and 5,7-di(methylsulfinyl)xanthone-2-carboxylic acid are illustrated as representative compounds.

This is a division of application Ser. No. 558,023, filed Mar. 13, 1975,which is in turn a division of application Ser. No. 431,794, filed Jan.8, 1974, now U.S. Pat. No. 3,894,049, which is in turn a cont.-in-partof application Ser. No. 259,852, filed June 5, 1972, now abandoned, inturn a cont.-in-part of application Ser. No. 217,287, filed Jan. 12,1972, now U.S. Pat. No. 3,849,565.

The present invention is directed to novel disubstituted xanthonecarboxylic acid compounds and to compositions containing and methodsutilizing these compounds as the essential ingredient in the treatmentof symptoms associated with allergic manifestations, for example,asthmatic conditions.

In a first aspect, the present invention relates to novel C-5,7disubstituted xanthone-2-carboxylic acid compounds selected from thoserepresented by the following formulas: ##SPC1##

And the pharmaceutically acceptable, non-toxic ester, amides, and saltsthereof;

WHEREIN THE R¹ groups are identical and selected from 1-hydroxyloweralkyl and the lower alkyl, cycloalkyl, tetrahydrofuran-2-yl,tetrahydropyran-2-yl, tetrahydropyran-4-yl, and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl; and the group ##STR1## IN WHICH N IS THEINTEGER 1 OR 2, R is lower alkyl when n is 1 and R is lower alkyl,hydroxy, amino, monolower alkylamino, or dilower alkylamino when n is 2;and

ONE R² group is selected from alkyl and alkoxy and the other R² group isselected from 1-hydroxylower alkyl and the lower alkyl, cycloalkyl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-1-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl; and the group ##STR2## IN WHICH EACH OFN AND R is as defined above.

Thus included within the scope of the present invention are:

1. THE C-5,7 disubstituted xanthone-2-carboxylic acid compounds whereinthe substituents are identical and as defined by R¹ above, and

2. THE C-5,7 disubstituted xanthone-2-carboxylic acid compounds whereinthe substituents are different and as defined by R² above.

Those of class (1) include the 5,7-di(1-hydroxyloweralkyl)xanthone-2-carboxylic acid compounds and the lower alkyl,cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyran-2-yl,tetrahydropyran-4-yl and 4-alkoxytetrahydropyran-4-yl ethers (preferablymethoxy) and esters (preferably acetoxy) thereof;

5,7-DI(LOWER ALKANOYL)XANTHONE-2-CARBOXYLIC ACID COMPOUNDS,

5,7-DI(LOWER ALKYL SULFINYL)XANTHONE-2-CARBOXYLIC ACID COMPOUNDS,

5,7-DI(LOWER ALKYL SULFONYL)XANTHONE-2-CARBOXYLIC ACID COMPOUNDS,

5,7-DI(SULFO)XANTHONE-2-CARBOXYLIC ACID COMPOUNDS,

5,7-DI(SULFAMOYL)XANTHONE-2-CARBOXYLIC ACID COMPOUNDS,

5,7-DI(N-monolower alkyl sulfamoyl)xanthone-2-carboxylic acid compounds,and

5,7-di(N,N-dilower alkyl sulfamoyl)xanthone-2-carboxylic acid compounds,represented respectively by the following formulas A-1 to A-6: ##SPC2##

and the pharmaceutically acceptable, non-toxic esters, amides, and saltsthereof; wherein R' is hydrogen, lower alkyl, cycloalkyl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl,4-alkoxytetrahydropyran-4-yl, or caboxylic acyl containing up to 12carbon atoms; and each R³, each R⁴, each R⁵, and each R⁶ is lower alkyland each R⁷ is hydrogen or lower alkyl.

Those of class 2) include the 5-alkyl-7-(R⁸)-xanthone-2-carboxylic acidcompounds, 5-alkoxy-7-(R⁸)-xanthone-2-carboxylic acid compounds,7-alkyl-5-(R⁸)-xanthone-2-carboxylic acid compounds and7-alkoxy-5-(R⁸)-xanthone-2-carboxylic acid compounds, wherein R⁸ is1-hydroxylower alkyl and the lower alkyl, cycloalkyl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof (preferably methoxy ether and acetoxy ester); loweralkanoyl; lower alkylsulfinyl; lower alkylsulfonyl; sulfo; sulfamoyl;N-monolower alkylsulfamoyl; or N,N-dilower alkylsulfamoyl; representedrespectively by the following formulas B-1 to B-4: ##SPC3##

and the pharmaceutically acceptable, non-toxic esters, amides, and saltsthereof; wherein R⁸ is as defined above, and each of R⁹, R¹⁰, R¹¹, andR¹² is alkyl.

In a second aspect, the present invention is directed to a method usefulfor relieving symptoms associated with allergic manifestations such asare brought about by antigen-antibody (allergic) reactions. In therelief of these symptoms, the method hereof serves to inhibit theeffects of the allergic reaction when administered in an effectiveamount. While not intending to be bound by any theoretical mechanism ofaction, the method hereof is believed to operate by inhibiting therelease and/or the action of toxic products, e.g. histamine,5-hydroxytryptamine, slow releasing substance (SRS-A), and others, whichare produced as a result of a combination of specific antibody andantigen (allergic reaction). These properties make the subject compoundsparticularly useful in the treatment of various allergic conditions.

The compounds of the present invention are also smooth muscle relaxants,e.g. bronchial dilators, and are therefore useful in the treatment ofconditions in which such agents may be indicated, as for instance, inthe treatment of broncho-constriction. The compounds of the presentinvention are also vasodilators and are therefore useful in thetreatment of conditions in which such agents may be indicated, as forinstance, in renal and cardiac disorders.

This aspect of the present invention thus relates to a method useful forinhibiting the effects of the allergic reaction which comprisesadministering an effective amount of a compound selected from thoserepresented by the following formulas: ##SPC4##

and the pharmaceutically acceptable, non-toxic esters, amides, and saltsthereof;

wherein the R¹ groups are identical and selected from 1-hydroxyloweralkyl and the lower alkyl, cycloalkyl, tetrahydrofuran-2-yl,tetrahydropyran-2-yl, tetrahydropyran-4-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl; and the group ##STR3## in which n is theinteger 1 or 2, R is lower alkyl when n is 1 and R is lower alkylhydroxy, amino, monolower alkylamino, or dilower alkylamino when n is 2;and

one R² group is selected from alkyl and alkoxy and the other R² group isselected from 1-hydroxylower alkyl and the lower alkyl, cycloalkyl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl, and the group ##STR4## in which each ofn and R is as defined above; or a pharmaceutically acceptable non-toxiccomposition incorporating said acids, esters, amides or salts as anessential ingredient.

The present invention, in a third aspect, is directed to pharmaceuticalcompositions useful for inhibiting the effects of the allergic reactioncomprising an effective amount of a compound selected from thoserepresented by the following formulas: ##SPC5##

and the pharmaceutically acceptable, non-toxic esters, amides, and saltsthereof;

wherein the R¹ groups are identical and selected from 1-hydroxyloweralkyl and the lower alkyl, cycloalkyl, tetrahydrofuran-2-yl,tetrahydropyran-2-yl, tetrahydropyran-4-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl, and the group ##STR5## in which n is theinteger 1 or 2, R is lower alkyl when n is 1 and R is lower alkyl,hydroxy, amino, monolower alkylamino, or dilower alkylamino when n is 2;and

one R² group is selected from alkyl and alkoxy and the other R² group isselected from 1-hydroxylower alkyl and the lower alkyl, cycloalkyl,tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl and4-alkoxytetrahydropyran-4-yl ethers thereof and the carboxylic acylesters thereof; lower alkanoyl, and the group ##STR6## in which each ofn and R is as defined above; in admixture with a pharmaceuticallyacceptable non-toxic carrier.

In the practice of the method of the present invention, an effectiveamount of a compound of the present invention or pharmaceuticalcompositions thereof, as defined above, is administered via any of theusual and acceptable methods known in the art, either singly or incombination with another compound or compounds of the present inventionor other pharmaceutical agents, such as antibiotics, hormonal agents,and so forth. These compounds or compositions can thus be administeredorally, topically, parenterally, or by inhalation and in the form ofeither solid, liquid, or gaseous dosages including tablets, suspensions,and aerosols, as discussed in more detail hereinafter. Theadministration can be conducted in single unit dosage form withcontinuous therapy or in single dose therapy ad libitum. In thepreferred embodiments, the method of the present invention is practicedwhen relief of symptoms is specifically required, or, perhaps, imminent;however, the method hereof is also usefully practiced as continuous orprophylactic treatment.

In view of the foregoing as well as in consideration of the degree ofseverity of the condition being treated, age of subject, and so forth,all of which factors being determinable by routine experimentation byone skilled in the art; the effective dosage in accordance herewith canvary over a wide range. Generally, an effective amount ranges from about0.005 to about 100 mg. per kg. of body weight per day and preferablyfrom about 0.01 to about 100 mg. per kg. of body weight per day. Inalternate terms, an effective amount in accordance herewith generallyranges from about 0.5 to about 7000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids, or gases. Thus, the compositions cantake the form of tablets, pills, capsules, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, and the like.The carriers can be selected from the various oils including those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly for injectable solutions. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, sucrose,gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,sodium stearate, glyceryl monostearate, sodium chloride, dried skimmilk, glycerol, propylene glycol, water, ethanol, and the like. Suitablepharmaceutical carriers and their formulation are described in"Remingtons Pharmaceutical Sciences" by E. W. Martin. Such compositionswill, in any event, contain an effective amount of the active compoundtogether with a suitable amount of carrier so as to prepare the properdosage form for proper administration to the host.

The compounds of the present invention demonstrate activity asinhibitors of the effects of the allergic reaction as measured by testsindicative of such activity involving passive cutaneous anaphylaxis assubstantially described, for example, by J. Goose et al., Immunology,16, 749 (1969).

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC6##

wherein each of R⁵ and R⁶ is as above defined; halo is bromo, chloro,fluoro, or iodo, preferably bromo; and each of R¹³ and R¹⁴ is loweralkyl, R¹⁴ being preferably methyl.

With reference to the above reaction sequence, an ortho, paradisubstituted (SR¹³) phenol (1) is condensed with the1,3-dicarbo(lower)alkoxy- 4-halobenzene compound (2) in the presence ofcuprous oxide optionally in organic liquid reaction medium, preferablyan organic amide such as dimethyl acetamide, dimethylformamide,N-methylpyrrolidone, tetramethylurea, and so forth, to prepare thecorresponding 1,3-dicarbo(lower)alkoxy-4-(o,p-disubstitutedphenyloxy)-benzene compound (3).

The reaction is preferably conducted in an inert organic reactionmedium, such as those listed above, or suitable mixtures of one or moreof such media. The reaction is further conducted at temperatures rangingfrom about 80° to about 220° C, preferably from about 120° to 200° C,and for a period of time sufficient to complete the reaction, rangingfrom about two hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of thesubstituted phenol per mole of the dicarbo(lower)carboxyhalobenzene perhalf mole of cuprous oxide. However, the amounts of the reactants to beemployed are not critical, some of the desired compound (3) beingobtained when employing any proportions thereof. In the preferredembodiments the reaction is conducted by reacting from about one toabout three moles of the substituted phenol compound with about from oneto about 1.2 moles of the dicarbo(lower)carboxyhalobenzene compound inthe presence of from about 0.5 to about 0.6 moles of the cuprous oxide.The inert organic reaction medium, if employed, is used in solventamounts.

Thereafter, the prepared compound (3) is base hydrolyzed to give thecorresponding 1,3-dicarboxy-4-(o,p-disubstituted phenyloxy)-benzene (4).The base hydrolysis conditions can be any employed conventionally in theart. Generally, the hydrolysis reaction is conducted using an alkalimetal hydroxide at about 50° to about 90° C and for a period of timesufficient to complete the reaction, ranging from about 15 minutes toabout 60 minutes, preferably in the presence of inert organic reactionmedia such as these normally employed in organic chemical reactions ofthis type, e.g. aqueous alkanol solutions. Although 2 moles of base arerequired per mole of compound (3), the amounts employed are not criticalto produce the desired hydrolysis. Preferably from about 3 to about 5moles of base are employed per mole of compound (3) and the reactionmedia, if employed, is used in solvent amounts.

The thus prepared diacid compound (4) is then cyclized with phosphorylchloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or,preferably, polyphosphoric acid (PPA), to give the corresponding5,7-disubstituted xanthone-2-carboxylic acid compound (5). The reactionis preferably, but optionally, conducted in an inert organic reactionmedium including those usually employed in organic chemical reactions,such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth.The reaction is further conducted at temperatures ranging from about 60°to about 180° C, and for a period of time sufficient to complete thereaction ranging from about 15 minutes to about 90 minutes.

Although the reaction consumes the reactants on the basis of one mole ofcompound (4) per mole of cyclizing reagent, the reaction can beperformed using any proportions of reactants. In the preferredembodiments, however, the reaction is conducted using from about 20 toabout 50 moles of the cyclizing reagent per mole of starting compound(4).

The 5,7-di(lower alkylthio)xanthone-2-carboxylic acid compounds (5) thusprepared are then esterified (R¹⁴) to give compounds (6) and the latterare oxidized followed by ester hydrolysis or compounds (5) are oxidizedto give the 5,7-di(lower alkylsulfinyl)- and 5,7-di(loweralkylsulfonyl)xanthone2-carboxylic acid compounds (A-3) and (A-4).

The esterification (5→6) is conducted with ethereal diazoalkane or witha lower alkanol in the presence of a trace of sulfuric acid at reflux.Hydrolysis of the esters, if necessary, is conducted as described abovefor the conversion of compounds 3→4.

The oxidation of compounds 5 or 6 when conducted with a peracid, such asperacetic acid, m-chloroperbenzoic acid, p-nitroperbenzoic acid,perphthalic acid, and so forth, yields the corresponding 5,7-di(loweralkylsulfinyl) acid compounds (A-3). The oxidation is preferablyconducted in liquid reaction media such as a chlorinated hydrocarbon,e.g. chloroform, methylene chloride, and carbon tetrachloride. Thereaction is conducted at temperatures ranging from about -10° to about60° C, preferably from about 0° to about 30° C and for a period of timesufficient to complete the reaction, ranging from about 1 hour to about6 hours. In the preferred embodiments, the reaction is conducted byreaction with from about 1 to about 1.1 moles of peracid.

Alternatively, the oxidation of compounds 5 or 6 with excess hydrogenperoxide gives the 5,7-di(lower alkylsulfonyl) acid compounds (A-4). Theperoxide oxidation is preferably conducted in liquid reaction media suchas a lower carboxylic acid, e.g. acetic acid and propionic acid. Thereaction is further conducted at temperatures ranging from about 20° toabout 100° C, preferably from 80° to about 90° C and for a period oftime sufficient to complete the reaction, ranging from about 30 minutesto about 3 hours. In the preferred embodiments, the reaction isconducted by reaction of from about 5 to about 10 moles of hydrogenperoxide per mole of starting compound.

In said oxidation steps, and particularly that employing peracid, amixture of products (A-3) and (A-4) may be obtained. If obtained, themixture can be conventionally separated, such as via chromatography, ifdesired, to isolate the respective oxidized products.

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC7##

wherein each of halo, R⁷ and R¹⁴ is as above defined.

With reference to the above reaction sequence, the5,7-dihydroxyxanthone-2-carboxylic acid esters (12) are prepared asdescribed above in Sequence A for compounds 1→6 including the step(10→11) of hydrolyzing the methyl ethers with hydrobromic or hydroiodicacid and acetic acid, preferably at temperatures of from about 100° toabout 160° C. Thereafter, compounds (12) are treated with adialkylthiocarbamoyl chloride, such as dimethylthiocarbamoyl chloride,in the presence of base, such as an alkali metal hydride, and in organicliquid reaction media, preferably an organic amide such as those listedabove with respect to reaction (1 + 2→3) to afford the products (13).The reaction is conducted at temperatures ranging from about 20° toabout 100° C, preferably from about 60° to about 80° C and for a periodof time sufficient to complete the reaction, ranging from about 1 hourto about 6 hours. In the preferred embodiments, the reaction isconducted by reaction of from about 2.2 to about 3.0 moles ofdialkylthiocarbamoyl chloride per mole of compound (12).

The product compounds (13) are then rearranged by reaction at atemperature of from about 200° to about 250° C, preferably from about220° to about 230° C, and for a period of time ranging from about 1 hourto about 8 hours and in the presence of organic medium such assulfolane, nitrobenzene, triethyleneglycol, and so forth, which ispreferably employed in solvent amounts, to give compounds (14).

Compounds (14) are then converted to the corresponding 5,7-dimercaptoacid compounds (15) by base hydrolysis such as those described above forthe preparation of compounds (4) from (3).

Compounds (15) are treated with excess chlorine under acidic conditionsto afford compounds (16). This reaction is conducted employing a pH ofabout 1 by use of hydrochloric acid, optionally in acetic acid solution.The reaction is further conducted at temperatures ranging from about 20°to about 100° C, preferably from 50° to about 60° C and for a period oftime sufficient to complete the reaction, ranging from about 2 hours toabout 12 hours.

Compound (16) is then reacted with a base, such as alkali metalhydroxide, preferably under aqueous conditions and at a temperatureranging from about 20° to about 100° C, preferably from 80° to about 90°C and for a period of from about one hour to about two hours andacidified to give the 5,7-disulfo-substituted acid compound (A-5).

Compounds (16) can be treated with ammonia, monolower alkylamine, ordilower alkylamine to give the 5,7-disulfamoyl, -di(monoloweralkyl)sulfamoyl, and -di(dilower alkyl)sulfamoyl acid compounds (A-6).This reaction is conducted at temperatures ranging from about 0° toabout 80° C, preferably from 20° to about 30° C, and for a period oftime sufficient to complete the reaction, ranging from about 1 hour toabout 8 hours. In the preferred embodiments, the reaction is conductedby reaction of from about 10 to about 20 moles of amine per mole ofcompound (16). This reaction is further conducted in organic reactionmedia such as those described above, preferably tetrahydrofuran,dioxane, dimethylsulfoxide, and so forth.

The C-5,7 di(chlorosulfonyl)xanthone-2-carboxylic acid compound (16) isa novel intermediate useful as described above.

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC8##

wherein each of halo, R¹⁴, R³, and R⁴ is as above defined and R¹⁵ islower alkyl.

With reference to the above reaction sequence, the5,7-dialkylxanthone-2-carboxylic acid compounds (20) are prepared asdescribed above in Sequence A for compounds 1→6. Thereafter, compounds(20) are oxidized with chromic oxide in acetic acid, acetic anhydride togive the 5,7-di(loweralkanoyl) compounds (A-2) which can be reduced tothe 5,7-di-(1-hydroxyloweralkyl) compound (A-1) with sodium borohydride.

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC9##

wherein each of halo, R¹⁴, R⁵, and R⁶ is as above defined; R¹⁶ is alkylor alkoxy; and R¹⁷ is lower alkyl.

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC10##

wherein each of halo, R¹⁴, R⁵, and R⁶ is as above defined, R¹⁸ is alkylor alkoxy; and R¹⁹ is lower alkyl.

With reference to the above reaction sequences D and E, the 5-alkyl oralkoxy-7-lower alkylthio compounds (24) and corresponding 5-loweralkylthio-7-alkyl or alkoxy compounds (29) are prepared as describedabove in Sequence A for compounds 1→6. Thereafter, the respectiveproducts are oxidized to the sulfinyl and sulfonyl compounds (B-1,2) and(B-3,4) either directly or through the acid esters (25) and (30), and asdescribed above for compounds 5→6→A-3 and A-4.

Sequence D'

Alternatively, the compounds of formula (24) wherein R¹⁶ is the methoxygroup are converted the compounds of formulas (B'-2) in accordance withthe following reaction sequence: ##SPC11##

wherein each of R¹⁷, R¹⁴, R⁵ and R⁶ is as above defined; and R¹⁶ ^(') isa higher alkyl group containing from 6 to 12 carbon atoms.

Sequence E'

Alternatively, the compounds of formula (29) wherein R¹⁸ is the methoxygroup are converted to the compounds of formulas (B'-4) in accordancewith the following reaction sequence: ##SPC12##

wherein each of R¹⁹, R¹⁴, R⁵ and R⁶ is as above defined; and R¹⁸ ^(') isa higher alkyl group containing from 6 to 12 carbon atoms.

With reference to the above reaction sequences D' and E', the5-methoxy-7-lower alkylthio compounds (24') and 5-loweralkylthio-7-methoxy compounds (29') are converted to their corresponding5-hydroxy-7-lower alkylthio compounds (61) and 5-loweralkylthio-7-hydroxy compounds (66) by treatment with hydriodic orhydrobromic acid in the presence of a suitable solvent, e.g., aceticanhydride, acetic acid or propionic acid. The compounds of formulas (61)and (66) are then esterified with an alkyl halide, e.g., methyl iodide,ethyl bromide, and the like, in the presence of an organic solvent,e.g., dimethylformamide, dimethylacetamide, n-methylpyrrolidone, and thelike, and lithium carbonate, to obtain the ester compounds of formulas(62) and (67).

The 5-hydroxy-7-lower alkylthio ester compounds (62) and 5-loweralkylthio-7-hydroxy ester compounds (67) are etherified with a higheralkyl halide, preferably a higher alkyl bromide, e.g., 1-bromohexane(hexyl bromide), 1-bromoheptane (heptyl bromide), 2-bromoheptane,1-bromooctane (octyl bromide), 1-bromododecane (dodecyl bromide),2-bromododecane, and the like, in the presence of an organic solvent,e.g., dimethylformamide, dimethylacetamide, acetone, and the like, andpotassium carbonate, to obtain the 5-higher alkoxy-7-lower alkylthioester compounds (63) and 5-lower alkylthio-7-higher alkoxy estercompounds (68), respectively.

The compounds of formulas (63) and (68) are oxidized to the sulfinylester compounds of formulas (64) and (69), and sulfonyl ester compounds,formulas (65) and (70), as described above for the oxidation of thecompounds of formula (6) to the compounds of formulas (A-3) and (A-4).The compounds of formulas (64) and (69) and 65) and (70) are thensubjected to base hydrolysis, according to the method described abovefor the conversion of the compounds of formula (3) to the compounds offormula (4), thus yielding the 5-higher alkoxy-7-lower alkylsulfinylacids of formula (B'-2) and 5-lower alkylsulfinyl-7-higher alkoxy acidsof formula (B'-4) and 5-higher alkoxy-7-lower alkylsulfonyl acids offormula (B'-2) and 5-lower alkylsulfonyl-7-higher alkoxy acids offormula (B'-4).

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC13##

wherein each of halo, R¹⁴ and R⁷ is as defined above and R²⁰ is alkyl oralkoxy.

With reference to the above reaction sequence, the 5- or 7-alkyl oralkoxy compounds (34) are prepared as described above in Sequence A forcompounds 1 6. Thereafter the 5- or 7-chlorosulfonyl compounds (35') and(35") are prepared by treating (34) with chlorosulfonic acid. Thisreaction is conveniently conducted in excess reagent at from about 100°to about 150° C and for a period of from about 2 to 4 hours. In thepreferred embodiments, amounts of chlorosulfonic acid ranging from about10 to about 25 moles per mole of starting compound are employed.

Thereafter, compounds (35') and (35") are converted to the sulfocompounds (B-1,2) or the sulfamoyl compounds (B-3,4), such as describedabove for the preparation of compounds (A-5) and (A-6).

Certain of the compounds of the present invention can be prepared inaccordance with the following reaction sequence: ##SPC14##

wherein each of halo, R¹⁴, R²⁰, R³, and R⁴ is as above defined, and Acylis lower alkanoyl, preferably acetyl.

With respect to the above reaction sequence, compound (34) is preparedas described in Sequence F. Thereafter the 9-oxo group is reduced suchas with potassium hydroxide in hydrazine, zinc and potassium hydroxidein ethanol, and the like, to prepare the corresponding C-5 or 7substituted xanthene-2-carboxylic acid (36). This compound is esterified(R¹⁴) as described above and the ester (37) then acylated with a loweralkanoyl chloride in the presence of aluminum chloride to give thecorresponding 5- or 7-lower alkanoyl compounds (38' and 38").

The compounds of formula (38' or 38") are reduced, such as with sodiumborohydride, to prepare the corresponding 1-hydroxylower alkyl compounds(41 42) which are acylated via conventional techniques and the acylatedcompounds are oxidized under Jones conditions to prepare thecorresponding 5- or 7-(1-acyloxylower alkyl) xanthone-2-carboxylic acidesters (43 and 44) which, when hydrolyzed under base conditions, givesthe corresponding 5- or 7-(1-hydroxylower alkyl) xanthone-2-carboxylicacids (B-1,2 and B-3,4).

Compounds (38' and 38") can be oxidized, such a via the Jones oxidation,to give (39 and 40) which are hydrolyzed to give the 5- or 7-loweralkanoylxanthone-2-carboxylic acids (B-1,2 and B-3,4).

Further methods by which certain of the compounds of the presentinvention can be prepared are as set forth in the following reactionsequences (H to K): ##SPC15##

wherein each of R¹³, R¹⁴, R¹⁵, and halo is as above defined and R²¹ isalkyl.

With reference to the above reaction sequences, Sequence H provides analternate method by which compounds (5), useful as described in SequenceA, are prepared from compound (15) of Sequence B. Sequence I provides analternate method by which compounds (16), useful as described inSequence B, are prepared from compound (15) of Sequence B through thexanthene sequence as described in Sequence G. Sequence J provides amethod for preparing the 5-lower alkyl-7-hydroxy compounds (51) whichare useful as described in Sequence B. Sequence J is also useful forpreparing the corresponding 7-lower alkyl-5-hydroxy compounds, useful asdescribed in Sequence B. Sequence K describes the preparation of the5-methoxy-7-alkyl compounds (55) and is also useful for preparing the5-alkyl-7-methoxy compounds, each of which is useful as described inSequence C.

An alternative basic method by which certain of the compounds hereof canbe prepared, as depicted above, is depicted as follows: ##SPC16##

wherein halo is as above defined and R²² at ortho or para or bothpositions is alkoxy.

With reference to Sequence L, an appropriate phenol (56) is treated with1,3-dimethyl-4-halo- (preferably iodo) benzene (57), as described above,to prepare the corresponding 1,3 -dimethyl-4-phenyloxybenzene (58). Thiscompound is then oxidized such as with potassium permanganate in aqueoust-butanol to give (59). This compound is then cyclized, as describedabove, to give the corresponding xanthone-2-carboxylic acid (60) whichcan be treated variously as described above, to prepare certain of thecompounds of the present invention.

The starting compounds for use in the present invention are known andcan be prepared by processes known per se. Thus, the1,3-dicarbo(lower)alkoxy-4-halobenzene starting compounds (2) areconveniently prepared by oxidizing 1,3-dimethyl-4-halobenzene(4-halo-m-xylene) with potassium permanganate, as described above (58→59), followed by conventional esterification. Theo,p-diloweralkylthiophenol compounds (1) are conveniently prepared bytreating o-hydroxybenzoic acid with excess chlorosulfonic acid to givethe corresponding o-hydroxy-m,m-di(chlorosulfonyl)-benzoic acid. This isreduced to the corresponding dimercapto compound with zinc and hydrogenchloride in acetic acid. The resultant compound is dialkylated withlower alkyl halide and potassium carbonate in dimethylformamide or withdialkylsulfate in aqueous sodium hyrdoxide to giveo-alkoxy-m,m-di(alkylthio)-benzoic acid. The latter is decarboxylatedwith heating in the presence of copper and quinoline and the resultantcompound selectively hydrolized with pyridine hydrochloride or withhydrogen bromide in acetic acid to give the o,p-di(loweralkylthio)-phenol.

The o,p-dialkoxyphenol starting compounds, i.e. (7), are prepared bytreating o,p-dihydroxyacetophenone with an appropriate alkyl halide andpotassium carbonate in dimethylformamide to give the correspondingdialkoxy compound. The latter is treated under Baever-Villigerconditions with peracid, e.g. peracetic or m-chloroperbenzoic acid, inchloroform containing p-toluenesulfonic acid to give1-acetoxy-2,4-dialkoxybenzene. The latter is hydrolized to give theo,p-diloweralkoxyphenol compounds.

The o,p-diloweralkylphenol starting compounds, i.e. (17), are preparedby treating 1,3-dialkylbenzene with acetyl chloride and aluminumchloride to give the corresponding acetyl compound followed by aBaeyer-Villiger reaction and hydrolysis or by treating1,3-dialkylbenzene with nitric acid and sulfuric acid to give the1-nitro-2,4-dialkylbenzene, reduction of the latter with stannouschloride to the amine, treatment thereof with sodium nitrite in HClfollowed by treatment with dilute sulfuric acid and heat to give theo,p-dialkylphenols.

The o-alkyl or -alkoxy-p-alkylthiophenol starting compounds, i.e., (21)wherein the R¹⁶ group contains from 1 to 12 carbon atoms, areconveniently prepared by treating an o-alkyl or -alkoxyphenol in whichthe alkyl or alkoxy group contains from 1 to 12 carbon atoms withchlorosulfonic acid in chloroform, followed by reduction with zinc --HCl in acetic acid, followed by alkylation, all as described above (cf.preparation of (1) or by treatment of an o-alkyl or -alkoxyphenol withdialkylsulfoxide and gaseous hydrogen chloride to give the corresponding3-alkyl or -alkoxy-4-hydroxybenzene dialkylsulfonium chloride. Thelatter is heated to give the corresponding o-alkyl or-alkoxy-p-alkylthiophenol product.

The o-alkylphenol used as the starting material in preparing the o-alkylcompounds of e.g. formula (21) is prepared by treating phenol with analkanoyl chloride (e.g. n-octanoyl chloride) to obtain the correspondingphenyl alkanoate (e.g. phenyl n-octanoate) which is then treated withaluminum chloride at 150° C to obtain predominantly the o-alkanoylphenol (e.g. o-n-octanoyl phenol) which is removed from any p-isomerwhich may be present by steam distillation. The o-alkanoyl phenol (e.g.o-n-octanoyl phenol) is then reduced with zinc amalgamhydrochloric acidto obtain the o-alkyl phenol (e.g. o-n-octyl phenol).

The corresponding o-alkylthio-p-alkyl or -alkoxyphenol startingcompounds, i.e. (26) wherein the R¹⁶ group contains from 1 to 12 carbonatoms, are prepared by treating a p-alkyl or -alkoxyphenol in which thealkyl or alkoxy group contains from 1 to 12 carbon atoms withchlorosulfonic acid, followed by reduction, alkylation, all as describedabove, provides the desired compounds.

The p-alkyl phenol used as the starting material in preparing thep-alkyl compounds of e.g. formula (26) is prepared by treating phenolwith an alkanoyl chloride (e.g. n-octanoyl chloride) to obtain thecorresponding phenyl alkanoate (e.g. phenyl n-octanoate) which is thentreated with aluminum chloride at 25° C and in the presence ofnitrobenzene to obtain predominantly p-alkanoyl phenol (e.g.p-n-octanoyl phenol) which is then purified by steam distillation toremove any o-isomer which may be present. The p-alkanoyl phenol (e.g.p-n-octanoyl phenol) is then reduced with zinc amalgam-hydrochloric acidto obtain the p-alkyl phenol (e.g. p-n-octyl phenol).

The o-alkyl-p-alkoxyphenol starting compound, i.e. (47), is prepared bytreating 1-alkyl-3-alkoxybenzene under Friedel-Crafts conditions to givethe corresponding acetyl compound followed by a Baeyer-Villiger reactionand hydrolysis, all as described above. Alternatively, p-alkoxyphenolstarting compounds can be acetylated ortho to the hydroxy group andresultant compound reduced. The o-alkoxy-p-alkylphenol startingcompounds are prepared from o-alkoxyphenols via p-acetylation andreduction, all as described above.

The carboxylic acyl esters of the secondary hydroxy alkyl substitutedcompounds (i.e. R'=carboxylic acyl and R⁸ = carboxylic acyl of 1-hydroxyalkyl) are prepared as described above or by secondary alcoholesterification methods known per se. One such method involves treatingthe 1-hydroxy alkyl products represented by Formulas A-1', B-1,2 andB-3,4 of Sequences C and G with a carboxylic acid chloride or carboxylicacid anhydride in the presence of a base, preferably pyridine, attemperatures ranging from about 60° to about 90° C and for a period oftime ranging from about 1 to about 2 hours to give the correspondingsecondary carboxylic acyloxy alkyl substituted xanthone-2-carboxylicacid compound.

The alkyl and cycloakyl ethers of the secondary hydroxyalkyl series(R'=alkyl, cycloalkyl and R⁸ =alkyl, cycloalkyl ethers of 1-hydroxyalkyl) are prepared by treatment of the xanthone acid ester with theappropriate alkyl- or cycloalkyl halide and sodium hydride in, e.g.dimethylformamide, followed by hydrolysis, as described above. Theetherification reaction is conducted at from about 50° to about 80° Cand for from about 1 to about 5 hours.

The t-butoxy ethers are prepared by treating the alcohol with isobutenein the presence of boron trifluoride and phosphoric acid in, e.g.methylene chloride, at temperatures of from about 10° to about 30° C andfor from 10 to about 24 hours, or more, followed by hydrolysis of theacid ester group, as described above.

The tetrahydrofuran-2-yloxy and tetrahydropyran-2 -yloxy ethers of the1-hydroxyalkyl compounds are prepared by treatment with dihydrofuran ordihydropyran in the presence of p-toluenesulfonic acid and organicreaction medium, e.g. benzene, at about room temperature up to reflux,for from about 2 to about 5 days, followed by hydrolysis of the acidester, as described above.

The 4-alkoxytetrahydropyran-4-yloxy ethers are prepared by treatment ofthe alcohol with 4-alkoxy-5,6-dihydro-2H-pyran, as described above forthe preparation of the furanyl and pyranyl ethers, followed by acidester hydrolysis. Treatment of the 4-alkoxytetrahydropyran-4-yloxy etherwith aluminum chloride and lithium aluminum hydride in organic reactionmedium affords the corresponding tetrahydropyran-4-yloxy ethers whichare oxidized to give the corresponding ethers in the xanthone acidseries. The latter can be directly prepared by treating the alcohol with4-bromotetrahydropyran and base. See Harrison and Harrison, Compendiumof Organic Synthetic Methods, Wiley-Interscience, New York (1971) 129and the references cited thereon.

The acid esters of the xanthone-2-carboxylic acids hereof are preparedas described above (e.g. 5→6) upon treatment of the acid with etherealdiazoalkane such as diazomethane and diazoethane or with the desiredlower alkyl iodide in the presence of lithium carbonate at roomtemperature or with the desired lower alkanol in the presence of a traceof sulfuric acid at reflux. The glycerol esters are prepared by treatingthe acid with thionyl chloride followed by treatment with a suitablyprotected ethylene glycol or propylene glycol (e.g. solketal) inpyridine, and hydrolyzing the protecting group of the ester thus formedwith dilute acid. In the sulfo series, the carboxylic acid esters arepreferably prepared with the desired lower alkanol in the absence ofacid catalyst.

The amides of the xanthone-2-carboxylic acids hereof are prepared bytreatment of the acids with thionyl chloride followed by treatment withanhydrous ammonia, alkyl, amine, dialkyl amine, dialkylaminoalkylamine,alkoxyalkylamine, or phenethylamine. In the lower alkyl sulfinyl series,the carboxylic acid amides are preferably prepared at the corresponding(lower alkylthio) stage followed by oxidation thereof, as describedabove.

The salts of the xanthone-2-carboxylic acids hereof are prepared bytreating the corresponding acids with pharmaceutically acceptable base.Representative salts derived from such pharmaceutically acceptable basesinclude the sodium, potassium, lithium, ammonia, calcium, magnesium,ferrous, ferric, zinc, manganous, aluminum, manganic, trimethylamine,triethylamine, tripropylamine, β-(dimethylamino)ethanol,triethanolamine, β-(diethylamino)ethanol, arginine, lysine, histidine,N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methyl glucamine, theobromine, purines, piperazine,piperidine, polyamine resins, caffeine, procaine salts. The reaction isconducted in an aqueous solution, alone or in combination with an inert,water miscible organic solvent, at a temperature of from about 0° C toabout 100° C, preferably at room temperature. Typical inert, watermiscible organic solvents include methanol, ethanol, isopropanol,butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal saltsare prepared, such as the calcium salts of magnesium salts of the acidsthe free acid starting material is treated with about one-half molarequivalent of pharmaceutically acceptable base. When the aluminum saltsof the acids are prepared, about one-third molar equivalent of thepharmaceutically acceptable base are employed.

In the preferred embodiment of the present invention, the calcium saltsand magnesium salts of the acids are prepared by treating thecorresponding sodium or potassium salts of the acids with at least onemolar equivalent of calcium chloride or magnesium chloride,respectively, in an aqueous solution, alone or in combination with aninert water miscible organic solvent, at a temperature of from about 20°C to about 100° C.

In the preferred embodiment of the present invention, the aluminum saltsof the acids are prepared by treating the acids with at least one-thirdmolar equivalent of an aluminum alkoxide, such as aluminum triethoxide,aluminum tripropoxide, and the like, in a hydrocarbon solvent, such asbenzene, xylene, cyclohexane, and the like at a temperature of fromabout 20° C to about 115° C.

In the sulfo series, use of one equivalent of base provides the sulfoacid monosalts; use of two equivalents provides the disalts.

In the present specification and claims, by the term "lower alkyl" isintended a lower alkyl group containing one to five carbon atomsincluding straight and branched chain groups and cyclic alkyl groups,for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl,cyclopropyl, cyclobutyl, and cyclopentyl. By the term "lower alkoxy" isintended the group "O-lower alkyl" wherein lower alkyl is as definedabove. The term "alkyl" as used herein is intended to include the loweralkyl groups as defined above and higher straight and branched chainalkyl groups containing from 6 to 12 carbon atoms, for example, n-hexyl,isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonanyl, n-decanyl,n-undecanyl, n-dodecanyl, and the like. By the term "alkoxy" is intendedthe group "O-alkyl" wherein alkyl is defined as above.

By the term "pharmaceutically acceptable, non-toxic esters, amides, andsalts" is respectively intended an alkyl or glycerol ester; anunsubstituted, monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl, orphenethyl substituted amide; and a salt as defined above.

The term "carboxylic acyl", as used herein, refers to thosephysiologically acceptable acyl groups, conventionally employed in thepharmaceutical art, preferably hydrocarbon carboxylic acyl. Included areacetate, propionate, butyrate, trimethylacetate, valerate,methylethylacetate, caproate, t-butylacetate, 3-methylpentanoate,enanthate, caprylate, triethylacetate, pelargonate, decanoate,undecanoate, benzoate, phenylacetate, diphenylacetate,cyclopentylpropionate, methoxyacetate, aminoacetate,diethylaminoacetate, trichloroacetate, β-chloropropionate,bicyclo[2.2.2]octane-1-carboxylate, adamantoate, dihydrogen phosphate,dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate, andthe like.

In the lower alkyl sulfinyl series, the compounds possess a chiralcenter. The methods hereof generate each of the d and l and dl forms andeach is thus included within the scope hereof. If desired, the isomerscan be separated by conventional means such as forming the alkaloidsalts of the products and employing fractional crystallization.

The nomemclature herein is employed in accordance with ChemicalAbstracts, 58, Subject Index (1962, January-June).

The following examples illustrate the method by which the presentinvention can be practiced. Where necessary, examples are repeated toprovide starting material for subsequent examples.

EXAMPLE 1

A. A mixture of 4.188 g. of 1,3-dicarbomethoxy-4-bromobenzene, 3.2 g. ofo,p-di(methylthio)phenol, 1.32 g. of cuprous oxide in 20 ml. ofdimethylacetamide is heated to 160° C and maintained thereat withstirring and under a nitrogen atmosphere. After monitoring via tlcindicates the reaction is substantially complete, the reaction mixtureis diluted with water and extracted with diethylether:methylene chloride(3:1). The extracts are chromatographed on 150 g. of alumina and theuniform fractions combined to give1,3-dicarbomethoxy-4-(o,p-di(methylthio)phenyloxy)-benzene.

B. 1,3-Dicarbomethoxy-4-(o,p-di(methylthio)phenyloxy)-benzene (4 g.) iscombined with 150 ml. of 5% potassium hydroxide in methanol. Theresultant mixture is refluxed for 1 hour after which time it isacidified, cooled, and filtered, to give1,3-dicarboxy-4-(o,p-di(methylthio)phenyloxy)-benzene.

C. 2.5 Grams of 1,3-dicarboxy-4-(o,p-di(methylthio)phenyloxy)-benzene in20 ml. of concentrated sulfuric acid is stirred at 80° C for 1 hour.After this time, the reaction mixture is poured into 200 ml. of icewater and the resultant mixture is heated on a steam bath for 15minutes. The mixture is cooled and filtered with the precipitate beingwashed with water and then recrystallized from acetic acid to give5,7-di(methylthio)-xanthone-2-carboxylic acid.

The foregoing procedure can be practiced using an alternative1,3-dicarboloweralkoxy-4-halo starting compound, such as1,3-dicarbomethoxy-4-chloro-(or iodo)-benzene,1,3-dicarboethoxy-4-fluoro-benzene, 1,3-dicarboethoxy-4-bromobenzene,and the like, with similar results. Likewise, the foregoing procedurecan be practiced using an alternate 2,4 -dilower alkylthiophenolstarting compound to prepare the corresponding 5,7 -di(loweralkylthio)-xanthone-2-carboxylic acids, e.g.5,7-di(ethylthio)-xanthone-2-carboxylic acid,5,7-di(n-propylthio)-xanthone-2-carboxylic acid,5,7-di(isopropylthio)-xanthone-2-carboxylic acid,5,7-di(n-butylthio)-xanthone-2-carboxylic acid,5,7-di(isobutylthio)-xanthone-2-carboxylic acid,5,7-di(sec-butylthio)-xanthone-2-carboxylic acid,5,7-di(t-butylthio)-xanthone-2-carboxylic acid,5,7-di(n-pentylthio)-xanthone-2-carboxylic acid, and5,7-di(cyclopentylthio)-xanthone-2-carboxylic acid.

EXAMPLE 2

A mixture of four grams of 5,7-di(methylthio)-xanthone-2-carboxylicacid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in 50 ml.of dimethylformamide is stirred at room temperature for a period of 16hours. After this period of time, the reaction mixture is poured intodilute hydrochloric acid-ice and the resultant mixture extracted withethyl acetate. The extracts are filtered through alumina to give methyl5,7-di(methylthio)-xanthone-2-carboxylate which can be recrystallizedfrom methanol.

Similarly, the foregoing method is used to prepare the methyl esters ofthe other products of Example 1. By use of alternate lower alkyl iodidesin the above procedure, the corresponding lower alkyl esters of thesecompounds are prepared.

EXAMPLE 3

Methyl 5,7-di(methylthio)-xanthone-2-carboxylate (927 mg.) in 60 ml. ofmethylene chloride is cooled to 0° C (ice). m-Chloroperbenzoic acid (555mg.) is then added and the mixture is stirred at 0° C for 75 minutes.The reaction mixture is then filtered through alumina and washed withmethylene chloride to give methyl5,7-di(methylsulfinyl)-xanthone-2-carboxylate which can berecrystallized from benzene/heptane.

Methyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate (720 mg.), 75 ml.of ethanol, and 10 ml. of 5% sodium hydroxide are refluxed for 30minutes. The mixture is cooled, partially evaporated and acidified. Theprecipitate is filtered off, washed and dried to give5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid which can berecrystallized from acetic acid.

Likewise from the respective starting compounds are prepared thefollowing compounds:

5,7-di(isopropylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(ethylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(n-propylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(n-butylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(sec-butylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(isobutylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(t-butylsulfinyl)-xanthone-2-carboxylic acid,

5,7-di(n-pentylsulfinyl)-xanthone-2-carboxylic acid, and

5,7-di(cyclopentylsulfinyl)-xanthone-2-carboxylic acid.

The above procedure (paragraph one) can be practiced upon thecorresponding acid starting compounds of Example 1 to give the sameproducts, without the need of the final hydrolysis step.

EXAMPLE 4

Methyl 5,7-di(methylthio)-xanthone-2-carboxylate (764 mg.), 2 ml. ofhydrogen peroxide (30%), and 40 ml. of acetic acid are heated on thesteam bath (80° C) for 90 minutes. Tlc indicates the absence of startingmaterial. The mixture is diluted with 60 ml. of hot water, and themixture is cooled, the solid is filtered off and dried to give methyl5,7-di(methylsulfonyl)-xanthone-2-carboxylate which can berecrystallized from acetic acid/water.

Methyl 5,7-di(methylsulfonyl)-xanthone-2-carboxylate (660 mg.), 1 g. ofpotassium hydroxide, and 60 ml. of 80% aqueous ethanol are refluxed for30 minutes. The mixture is filtered, acidified, and the solid filteredoff to give 5,7-di(methylsulfonyl)-xanthone-2-carboxylic acid.

Likewise, from the respective starting compounds are prepared thefollowing compounds:

5,7-di(isopropylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(ethylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(n-propylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(n-butylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(sec-butylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(isobutylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(t-butylsulfonyl)-xanthone-2-carboxylic acid,

5,7-di(n-pentylsulfonyl)-xanthone-2-carboxylic acid, and

5,7-di(cyclopentylsulfonyl)-xanthone-2-carboxylic acid.

The above procedure (paragraph one) can be practiced upon thecorresponding acid starting compounds of Example 1 to give the sameproducts, without the need of the final hydrolysis step.

EXAMPLE 5

The compound 5,7-dimethoxyxanthone-2-carboxylic acid is prepared fromo,p-dimethoxyphenol according to the procedures (A), (B) and (C) ofExample 1.

A mixture of 11 g. of 5,7-dimethoxyxanthone-2-carboxylic acid in 100 ml.of concentrated aqueous hydrogen iodide and 100 ml. of acetic acid isrefluxed for 4 hours. After this time, the mixture is cooled, dilutedwith water, and filtered. The precipitate is washed and dried to give5,7-dihydroxyxanthone-2-carboxylic acid.

Alternatively, the hydroxy compound can be prepared according to theprocedure of Example 1.

Methyl 5,7-dihydroxyxanthone-2-carboxylate is prepared from the acid bythe procedure of Example 2.

To a solution of 6.2 g. of methyl 5,7-dihydroxyxanthone-2-carboxylate in100 ml. of dimethylformamide are added 1 g. of sodium hydride. Themixture is stirred for ten minutes at room temperature under nitrogen.Dimethylthiocarbamoyl chloride (3 g.) is then added thereto and theresultant mixture stirred at 70° C for 6 hours and then at roomtemperature for 16 hours. The mixture is then poured into 200 ml. ofwater containing 1 ml. of acetic acid, the resultant mixture is filteredand the solid dried to give methyl5,7-di(dimethylthiocarbamoyloxy)-xanthone-2-carboxylate.

Methyl 5,7-di(dimethylthiocarbamoyloxy)-xanthone-2-carboxylate (8 g.) in150 ml. of sulfolane is stirred at 230° C under nitrogen. After a totalof 6 hours under these conditions, tlc indicates the absence of startingmaterial. The mixture is cooled to 80° C and 150 ml. of hot water areslowly added. The mixture is then cooled and the filtered solid washedwith water and dried to give methyl5,7-di(dimethylcarbamoylthio)-xanthone-2-carboxylate.

Methyl 5,7-di(dimethylcarbamoylthio)-xanthone-2-carboxylate (7.5 g.), 10g. of potassium hydroxide and 250 ml. of 80% aqueous ethanol is refluxedfor 1 hour. After this time, 250 ml. of water are added and the mixtureis treated with charcoal, filtered, acidified. The product is filteredoff and dried to give 5,7-dimercaptoxanthone-2-carboxylic acid.

EXAMPLE 6

One gram of 5,7-dimercaptoxanthone-2-carboxylic acid is dissolved in 30ml. of acetic acid containing 3 ml. of concentrated hydrochloric acidunder warming. The solution is then saturated with chlorine gas andstirred at room temperature overnight. The solution is then diluted withwater and the precipitate filtered off, washed, and dried to give5,7-di(chlorosulfonyl)-xanthone-2-carboxylic acid.

EXAMPLE 7

The thus prepared chlorosulfonyl compound is then treated with aqueouspotassium hydroxide, as described in Example 5, last paragraph, to give5,7-disulfoxanthone-2-carboxylic acid.

EXAMPLE 8

A mixture of 1 g. of 5,7-chlorosulfonylxanthone-2-carboxylic acid, 2 ml.of concentrated aqueous ammonia, and 20 ml. of dioxane is stirred atroom temperature overnight. The mixture is then diluted with water,acidified, and the solid filtered off and dried to give5,7-di(sulfamoyl)-xanthone-2-carboxylic acid.

Upon substituting a primary amine, such as methylamine and ethylamine,or a secondary amine, such as dimethylamine and diethylamine, forammonia in the above method, the corresponding C-5,7-di(N-monoloweralkylsulfamoyl) and di(N,N-dilower alkylsulfamoyl) products areobtained, e.g.:

5,7-di(methylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(ethylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(n-propylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(isopropylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(dimethylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(diethylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(di-n-propylsulfamoyl)-xanthone-2-carboxylic acid,

5,7-di(di-isopropylsulfamoyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 9

The compounds 5,7-di(lower alkyl)-xanthone-2-carboxylic acid, e.g.:

5,7-diethylxanthone-2-carboxylic acid,

5,7-di-n-propylxanthone-2-carboxylic acid,

5,7-di-n-butylxanthone-2-carboxylic acid,

5,7-di-sec-butylxanthone-2-carboxylic acid,

5,7-di-n-pentylxanthone-2-carboxylic acid,

5,7-di-isopentylxanthone-2-carboxylic acid, and so forth are preparedfrom o,p-diloweralkylphenols according to the procedures (A), (B) and(C) of Example 1.

A suspension of 2.5 g. of 5,7-diethylxanthone-2-carboxylic acid and 5 g.of chromic oxide in 190 ml. of acetic acid and 10 ml. of aceticanhydride is stirred at room temperature for a period of 6 hours. Aftermonitoring the reaction by tlc indicates the absence of startingmaterial, 10 ml. of isopropanol are added and the resultant mixturewarmed on the steam bath. Water (200 ml.) is then added portionwise andthe resultant mixture is cooled to room temperature. The precipitate isfiltered off, washed, and dried to obtain5,7-diacetylxanthone-2-carboxylic acid.

Similarly, the other 5,7-dialkanoylxanthone-2-carboxylic acid compoundsare prepared, e.g.:

5,7-dipropionylxanthone-2-carboxylic acid,

5,7-di(n-butyryl)-xanthone-2-carboxylic acid,

5,7-di(sec-butyryl)-xanthone-2-carboxylic acid,

5,7-dipentanoylxanthone-2-carboxylic acid,

5,7-di(isopentanoyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 10

To a solution of three grams of 5,7-diacetylxanthone-2-carboxylic acidin 90 ml. of methanol are added 3 g. of sodium borohydride in 30 ml. ofwater at a temperature of from 25° to 30° C, with stirring over a periodof about 30 minutes. After 15 minutes, under these conditions, 50 ml. ofwater and 5 ml. of acetic acid are added and the resultant mixture isstripped of solvent. The resultant mixture is extracted with methylenechloride and washed with bicarbonate and water. The washed extracts areconcentrated to give 5,7-di(1-hydroxyethyl)xanthone-2-carboxylic acid.

Similarly, the other 5,7-(1-hydroxyalkyl)-xanthone-2-carboxylic acidcompounds are prepared, e.g.:

5,7-(1-hydroxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-(1-hydroxy-n-butyl)-xanthone-2-carboxylic acid,

5,7-(1-hydroxy-sec-butyl)-xanthone-2-carboxylic acid,

5,7-(1-hydroxy-n-pentyl)-xanthone-2-carboxylic acid,

5,7-(1-hydroxy-isopentyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 11

The compounds 5-alkyl or-alkoxy-7-(lower-alkylthio)-xanthone-2-carboxylic acid, e.g.:

5-methyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-ethyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-propyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-isopropyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-butyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-isobutyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-sec-butyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-t-butyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-pentyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-isopentyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-hexyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-octyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-dodecyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-cyclopentyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-methoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-ethoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-propoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-butoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-isobutoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-sec-butoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-t-butoxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-pentyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-isopentyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-hexyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-dodecyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-cyclopentyloxy-7-(methylthio)-xanthone-2-carboxylic acid, and thecorresponding 5-substituted 28 compounds in each of the 7-ethylthio-,7-n-propylthio-, 7-isopropylthio-, 7-n-butylthio-, 7-isobutylthio-,7-sec-butylthio-, 7-t-butylthio, 7-n-pentylthio-, 7-isopentylthio-, and7-(cyclopentylthio)-xanthone-2-carboxylic acid series are preparedaccording to the procedures (A), (B) and (C) of Example 1.

The thus prepared compounds are treated in accordance with theprocedures of Examples 3 and 4 to prepare the corresponding5-substituted-7-loweralkylsulfinyl- and-7-loweralkylsulfonylxanthone-2-carboxylic acid compounds, to wit:

5-methyl-7-methylsulfinylxanthone-2-carboxylic acid,

5-methyl-7-methylsulfonylxanthone-2-carboxylic acid,

5-ethyl-7-methylsulfinylxanthone-2-carboxylic acid,

5-ethyl-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-propyl-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-propyl-7-methylsulfonylxanthone-2-carboxylic acid,

5-isopropyl-7-methylsulfinylxanthone-2-carboxylic acid,

5-isopropyl-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-octyl-7-methylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methoxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-methoxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-ethoxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-ethoxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-propoxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-propoxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-isopropoxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-isopropoxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-methyl-7-ethylsulfonylxanthone-2-carboxylic acid,

5-ethyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-ethyl-7-ethylsulfonylxanthone-2-carboxylic acid,

5-n-propyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-propyl-7-ethylsulfonylxanthone-2-carboxylic acid,

5-isopropyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-isopropyl-7-ethylsulfonylxanthone-2-carboxylic acid,

5-n-octyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-octyl-7-ethylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methoxy-7-ethylsulfinylxanthone-2-carboxylic acid,

5-methoxy-7-ethylsulfonylxanthone-2-carboxylic acid,

5-ethoxy-7-ethylsulfinylxanthone-2-carboxylic acid,

5-ethoxy-7-ethylsulfonylxanthone-2-carboxylic acid,

5-n-propoxy-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-propoxy-7-ethylsulfonylxanthone-2-carboxylic acid,

5-isopropoxy-7-ethylsulfinylxanthone-2-carboxylic acid,

5-isopropoxy-7-ethylsulfonylxanthone-2-carboxylic acid,

5-n-octyloxy-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-octyloxy-7-ethylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methyl-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-methyl-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-ethyl-7-n-propylsufinylxanthone-2-carboxylic acid,

5-ethyl-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-n-propyl-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-n-propyl-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-isopropyl-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-isopropyl-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-n-octyl-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-n-octyl-7-n-propylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methoxy-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-methoxy-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-ethoxy-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-ethoxy-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-n-propoxy-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-n-propoxy-7-n-propylsulfonylxanthone-2-carboxylic acid,

5-isopropoxy-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-isopropoxy-7n-propylsulfonylxanthone-2-carboxylic acid,

5-n-octyloxy-7-n-propylsulfinylxanthone-2-carboxylic acid,

5-n-octyloxy-7-n-propylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-methyl-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-ethyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-ethyl-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-n-propyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-propyl-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-isopropyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-isopropyl-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-n-octyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-octyl-7-isopropylsulfonylxanthone-2-carboxylic acid, and so forth,

5-methoxy-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-methoxy-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-ethoxy-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-ethoxy-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-n-propoxy-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-propoxy-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-isopropoxy-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-isopropoxy-7-isopropylsulfonylxanthone-2-carboxylic acid,

5-n-octyloxy-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-octyloxy-7-isopropylsulfonylxanthone-2-carboxylic acid, and soforth,

In a similar manner, the following compounds are also prepared:

5-n-butoxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-cyclopentyloxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-pentyloxy-7-methylsulfinylxanthone-12-carboxylic acid, and

5-isopentyloxy-7-methylsulfinylxanthone-2-carboxylic acid.

EXAMPLE 12

Example 11 is repeated to prepare the 5-(lower alkylthio)-7-alkyl or-alkoxy-xanthone-2-carboxylic acid compounds and the sulfinyl andsulfonyl compounds otherwise corresponding thereto, i.e.:

5-methylthio-7-methylxanthone-2-carboxylic acid,

5-methylthio-7-ethylxanthone-2-carboxylic acid,

5-methylthio-7-n-propylxanthone-2-carboxylic acid,

5-methylthio-7-isopropylxanthone-2-carboxylic acid,

5-methylthio-7-n-octylxanthone-2-carboxylic acid, and so forth,

5-methylthio-7-methoxyxanthone-2-carboxylic acid,

5-methylthio-7-ethoxyxanthone-2-carboxylic acid,

5-methylthio-7-n-propoxyxanthone-2-carboxylic acid,

5-methylthio-7-isopropoxyxanthone-2-carboxylic acid,

5-methylthio-7-n-octyloxyxanthone-2-carboxylic acid, and so forth, andthe corresponding total of 28 compounds in each of the 5-ethylthio-,5-n-propyl-, 5-n-propylthio-, 5-isopropylthio, and so forth series;

5-methylsulfinyl-7-methylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-methylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-ethylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-ethylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-n-propylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-propylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-isopropylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-isopropylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-octylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-methoxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-methoxyxanthone-2-carboxylic acid,

5-methylsulfinyl-7-ethoxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-ethoxyxanthone-2-carboxylic acid,

5-methylsulfinyl-7-n-propoxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-propoxyxanthone-2-carboxylic acid,

5-methylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-isopropoxyxanthone-2-carboxylic acid,

5-methylsulfinyl-7-octyloxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-octyloxyxanthone-2-carboxylic acid, and so forth,

5-ethylsulfinyl-7-methylxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-methylxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-ethylxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-ethylxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-n-propylxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-n-propylxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-isopropylxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-isopropylxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-n-octylxanthone-2-carboxylic acid, and so forth,

5-ethylsulfinyl-7-methoxyxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-methoxyxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-ethoxyxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-ethoxyxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-n-propoxyxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-n-propoxyxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-isopropoxyxanthone-2-carboxylic acid,

5-ethylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-ethylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid, and so forth,

5-n-propylsulfinyl-7-methylxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-methylxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-ethylxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-ethylxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-propylxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-n-propylxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-isopropylxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-isopropylxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-n-octylxanthone-2-carboxylic acid, and so forth,

5-n-propylsulfinyl-7-methoxyxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-methoxyxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-ethoxyxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-ethoxyxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-propoxyxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-n-propoxyxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-isopropoxyxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-n-propylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid, and so forth,

5-isopropylsulfinyl-7-methylxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-methylxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-ethylxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-ethylxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-n-propylxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-n-propylxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-isopropylxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-isopropylxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-n-octylxanthone-2-carboxylic acid, and so forth,

5-isopropylsulfinyl-7-methoxyxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-methoxyxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-ethoxyxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-ethoxyxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-n-propoxyxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-n-propoxyxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-isopropoxyxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-isopropoxyxanthone-2-carboxylic acid,

5-isopropylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-isopropylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid, and soforth.

EXAMPLE 13

The compounds 5-alkyl- or -alkoxyxanthone-2-carboxylic acid are preparedaccording to the procedures (A), (B) and (C) of Example 1.

5-Methylxanthone-2-carboxylic acid (2.5 g.) is dissolved in 15 ml. ofchlorosulfonic acid. After heating the mixture to 140° C for 3 hours, itis cooled (ice) and poured slowly into 50 ml. of 30% aqueous aceticacid. After cooling, the precipitate is filtered off, washed neutral anddried to give 5-methyl-7-chlorosulfonylxanthone-2-carboxylic acid.

In like manner, the following are prepared:

5-ethyl-7-chlorosulfonylxanthone-2-carboxylic acid,

5-n-propyl-7-chlorosulfonylxanthone-2-carboxylic acid,

5-isopropyl-7-chlorosulfonylxanthone-2-carboxylic acid,

5-n-octyl-7-chlorosulfonylxanthone-2-carboxylic acid,

5-methoxy-7-chlorosulfonylxanthone-2-carboxylic acid,

5-ethoxy-7-chlorosulfonylxanthone-2-carboxylic acid,

5-n-propoxy-7-chlorosulfonylxanthone-2-carboxylic acid,

5-isopropoxy-7-chlorosulfonylxanthone-2-carboxylic acid,

5-n-octyloxy-7-chlorosulfonylxanthone-2-carboxylic acid, and so forth.

The thus prepared compounds are treated in accordance with theprocedures of Example 7 to give the corresponding sulfo compounds, e.g.:

5-methyl-7-sulfoxanthone-2-carboxylic acid,

5-ethyl-7-sulfoxanthone-2-carboxylic acid,

5-n-propyl-7-sulfoxanthone-2-carboxylic acid,

5-isopropyl-7-sulfoxanthone-2-carboxylic acid,

5-n-octyl-7-sulfoxanthone-2-carboxylic acid,

5-methoxy-7-sulfoxanthone-2-carboxylic acid,

5-ethoxy-7-sulfoxanthone-2-carboxylic acid,

5-n-propoxy-7-sulfoxanthone-2-carboxylic acid,

5-isopropoxy-7-sulfoxanthone-2-carboxylic acid, and

5-n-octyloxy-7-sulfoxanthone-2-carboxylic acid,

or in accordance with the procedures of Example 8 to give thecorresponding sulfamoyl compounds, e.g.:

5-methyl-7-sulfamoylxanthone-2-carboxylic acid,

5-ethyl-7-sulfamoylxanthone-2-carboxylic acid,

5-n-propyl-7-sulfamoylxanthone-2-carboxylic acid,

5-isopropyl-7-sulfamoylxanthone-2-carboxylic acid,

5-n-octyl-7-sulfamoylxanthone-2-carboxylic acid,

5-methoxy-7-sulfamoylxanthone-2-carboxylic acid,

5-ethoxy-7-sulfamoylxanthone-2-carboxylic acid,

5-n-propoxy-7-sulfamoylxanthone-2-carboxylic acid,

5-isopropoxy-7-sulfamoylxanthone-2-carboxylic acid,

5-n-octyloxy-7-sulfamoylxanthone-2-carboxylic acid,

5-methyl-7-methylsulfamoylxanthone-2-carboxylic acid,

5-ethyl-7-methylsulfamoylxanthone-2-carboxylic acid,

5-n-propyl-7-methylsulfamoylxanthone-2-carboxylic acid,

5-isopropyl-7-methylsulfamoylxanthone-2-carboxylic acid,

5-n-octyl-7-methylsulfamoylxanthone-2-carboxylic acid,

5-methoxy-7-methylsulfamoylxanthone-2-carboxylic acid,

5-ethoxy-7-methylsulfamoylxanthone-2-carboxylic acid,

5-n-propoxy-7-methylsulfamoylxanthone-2-carboxylic acid,

5-isopropoxy-7-methylsulfamoylxanthone-2-carboxylic acid,

5-n-octyloxy-7-methylsulfamoylxanthone-2-carboxylic acid, and so forth,

5-methyl-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-ethyl-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-n-propyl-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-isopropyl-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-n-octyl-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-methoxy-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-ethoxy-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-n-propoxy-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-isopropoxy-7-dimethylsulfamoylxanthone-2-carboxylic acid,

5-n-octyloxy-7-dimethylsulfamoylxanthone-2-carboxylic acid, and soforth.

EXAMPLE 14

The procedure of Example 13 is repeated to prepare the corresponding5-chlorosulfonyl-, 5-sulfo- and 5-sulfamoyl- compounds in the 7-loweralkyl- or -lower alkoxy series, e.g.:

5-chlorosulfonyl-7-methylxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-ethylxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-n-propylxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-isopropylxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-n-octylxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-methoxyxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-ethoxyxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-n-propoxyxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-isopropoxyxanthone-2-carboxylic acid,

5-chlorosulfonyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-sulfo-7-methylxanthone-2-carboxylic acid,

5-sulfo-7-ethylxanthone-2-carboxylic acid,

5-sulfo-7-n-propylxanthone-2-carboxylic acid,

5-sulfo-7-isopropylxanthone-2-carboxylic acid,

5-sulfo-7-n-octylxanthone-2-carboxylic acid,

5-sulfo-7-methoxyxanthone-2-carboxylic acid,

5-sulfo-7-ethoxyxanthone-2-carboxylic acid,

5-sulfo-7-n-propoxyxanthone-2-carboxylic acid,

5-sulfo-7-isopropoxyxanthone-2-carboxylic acid,

5-sulfo-7-n-octyloxyxanthone-2-carboxylic acid,

5-sulfamoyl-7-methylxanthone-2-carboxylic acid,

5-sulfamoyl-7-ethylxanthone-2-carboxylic acid,

5-sulfamoyl-7-n-propylxanthone-2-carboxylic acid,

5-sulfamoyl-7-isopropylxanthone-2-carboxylic acid,

5-sulfamoyl-7-n-octylxanthone-2-carboxylic acid,

5-sulfamoyl-7-methoxyxanthone-2-carboxylic acid,

5-sulfamoyl-7-ethoxyxanthone-2-carboxylic acid,

5-sulfamoyl-7-n-propoxyxanthone-2-carboxylic acid,

5-sulfamoyl-7-isopropoxyxanthone-2-carboxylic acid,

5-sulfamoyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-methylxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-ethylxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-n-propylxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-isopropylxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-n-octylxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-methoxyxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-ethoxyxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-n-propoxyxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-isopropoxyxanthone-2-carboxylic acid,

5-methylsulfamoyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-methylxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-ethylxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-n-propylxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-isopropylxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-n-octylxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-methoxyxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-ethoxyxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-n-propoxyxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-isopropoxyxanthone-2-carboxylic acid,

5-dimethylsulfamoyl-7-n-octyloxyxanthone-2-carboxylic acid, and soforth.

EXAMPLE 15

To a solution of 25 g. of 7-methylxanthone-2-carboxylic acid in 200 ml.of triethylene glycol are added 18 g. of potassium hydroxide in 12.1 g.of 95% hydrazine. The resultant mixture is heated to reflux (155° C) andmaintained thereat for 1 hour. The distillate is removed and thetemperature is held at a temperature of about 200° C for 2 hours. Themixture is then cooled to 68° C and 200 ml. of water is added and theresultant solution poured into 110 ml. of water containing 60 ml. ofconcentrated hydrochloric acid. The resultant mixture is heated to 90°C, cooled to room temperature and filtered to give7-methylxanthene-2-carboxylic acid.

Twenty-six grams of 7-methylxanthene-2-carboxylic acid is added to 400ml. of absolute methanol. To the resultant solution are added 18 ml. ofconcentrated sulfuric acid and the mixture is then heated at reflux forabout 2 hours. The mixture is then cooled to 40° C and sufficient wateris added to bring the total volume to 1400 ml. The resultant mixture isthen filtered to give methyl 7-methylxanthene-2-carboxylate.

A mixture of 130 g. of methyl 7-methylxanthene-2-carboxylate in 200 ml.of dichloroethane is cooled to -5° C and to the cooled solution areadded 4.95 ml. of acetyl chloride and then 17.0 g. of aluminumtrichloride. The resultant solution is stirred at room temperature for1.75 hours. After this time, the solution is poured into a mixture of300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloricacid. The mixture is then extracted with three 500 ml. portions ofmethylene chloride. The combined extracts are washed with 10% aqueouspotassium hydroxide solution and the washed solution evaporated to givemethyl 5-acetyl-7-methylxanthene-2-carboxylate.

To a solution of 1.42 g. of methyl5-acetyl-7-methylxanthene-2-carboxylate in 120 ml. of acetone and 15 ml.of dimethylformamide are added 3.0 g. of magnesium sulfate and 2.5 ml.of 8 N chromic acid in 8 N sulfuric acid. The resultant mixture isstirred at room temperature for 50 minutes after which time a solutionof 4 g. of sodium bisulfite in 20 ml. of water are added. After thistime, 250 ml. of water and 25 ml. of sulfuric acid:water (1:1) areadded. The mixture is stripped of solvent and filtered. The precipitateis washed with 50 ml. of water to give methyl5-acetyl-7-methylxanthone-2-carboxylate which is recrystallized frommethanol (displacement from methylene chloride solution).

A solution of 2 g. of methyl 5-acetyl-7-methylxanthone-2-carboxylate in200 ml. of 10% aqueous, 10% potassium hydroxide in methanol is heated atreflux under a nitrogen atmosphere for 45 minutes. After this time, 20ml. of water are added and the resultant mixture heated at reflux for 35minutes. Water (300 ml.) is then added and the resultant mixtureacidified and filtered to give 5-acetyl-7-methylxanthone-2-carboxylicacid.

Upon using the appropriate acyl chloride reagent in the foregoingprocedure the other 5-acyl-7-methylxanthone-2-carboxylic acids, seeExample 9, can be prepared and the 5-acyl-7-alkyl- or -alkoxy compoundsare also thus prepared, e.g.:

5-propionyl-7-methylxanthone-2-carboxylic acid,

5-acetyl-7-ethylxanthone-2-carboxylic acid,

5-propionyl-7-ethylxanthone-2-carboxylic acid,

5-acetyl-7-n-propylxanthone-2-carboxylic acid,

5-propionyl-7-n-propylxanthone-2-carboxylic acid,

5-acetyl-7-isopropylxanthone-2-carboxylic acid,

5-propionyl-7-isopropylxanthone-2-carboxylic acid,

5-acetyl-7-n-octylxanthone-2-carboxylic acid,

5-propionyl-7-n-octylxanthone-2-carboxylic acid,

5-acetyl-7-methoxyxanthone-2-carboxylic acid,

5-propionyl-7-methoxyxanthone-2-carboxylic acid,

5-acetyl-7-ethoxyxanthone-2-carboxylic acid,

5-propionyl-7-ethoxyxanthone-2-carboxylic acid,

5-acetyl-7-n-propoxyxanthone-2-carboxylic acid,

5-propionyl-7-n-propoxyxanthone-2-carboxylic acid,

5-acetyl-7-isopropoxyxanthone-2-carboxylic acid,

5-propionyl-7-isopropoxyxanthone-2-carboxylic acid,

5-acetyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-propionyl-7-n-octyloxyxanthone-2-carboxylic acid, and the 5-butyryland 5-cyclopropylcarbonyl compounds corresponding thereto, and so forth.

EXAMPLE 16

The procedure of Example 15 is repeated with alternate startingcompounds to prepare the following:

5-methyl-7-acetylxanthone-2-carboxylic acid,

5-methyl-7-propionylxanthone-2-carboxylic acid,

5-ethyl-7-acetylxanthone-2-carboxylic acid,

5-ethyl-7-propionylxanthone-2-carboxylic acid,

5-n-propyl-7-acetylxanthone-2-carboxylic acid,

5-n-propyl-7-propionylxanthone-2-carboxylic acid,

5-isopropyl-7-acetylxanthone-2-carboxylic acid,

5-isopropyl-7-propionylxanthone-2-carboxylic acid,

5-n-octyl-7-acetylxanthone-2-carboxylic acid,

5-n-octyl-7-propionylxanthone-2-carboxylic acid,

5-methoxy-7-acetylxanthone-2-carboxylic acid,

5-methoxy-7-propionylxanthone-2-carboxylic acid,

5-ethoxy-7-acetylxanthone-2-carboxylic acid,

5-ethoxy-7-propionylxanthone-2-carboxylic acid,

5-n-propoxy-7-acetylxanthone-2carboxylic acid,

5-n-propoxy-7-propionylxanthone-2-carboxylic acid,

5-isopropoxy-7-acetylxanthone-2-carboxylic acid,

5-isopropoxy-7-propionylxanthone-2-carboxylic acid,

5-n-octyloxy-7-acetylxanthone-2-carboxylic acid,

5-n-octyloxy-7-propionylxanthone-2-carboxylic acid, and the 7-butyryland 7-cyclopropylcarbonyl compounds corresponding thereto, and so forth.

EXAMPLE 17

To a solution of 6 g. of methyl 5-acetyl-7-methyl-xanthene-2-carboxylatein 500 ml. of absolute methanol are added 1.1 g. of sodium borohydridein 50 ml. of water at a temperature of from 25° to 30° C with stirring,over a period of about 30 minutes. After 15 minutes under theseconditions, 400 ml. of water and 20 ml. of acetic acid are added and theresultant mixture is stripped of solvent. The resultant mixture isextracted with methylene chloride and washed with bicarbonate and water.The washed extracts are concentrated to give methyl5-(1-hydroxyethyl)-7-methylxanthene-2-carboxylate.

A solution of 5.5 g. of methyl5-(1-hydroxyethyl)-xanthene-7-methylxanthene-2-carboxylate in 100 ml. ofpyridine is cooled in an ice bath. To the cooled solution are added 2.91ml. of acetyl chloride and the resultant mixture is stirred in an icebath for one-half hour and then at room temperature for 1 hour. Afterthis time, the reaction mixture is poured into dilute hydrochloricacid-ice and the precipitate is filtered off and washed to give methyl5-(1-acetoxyethyl)-7-methylxanthene-2-carboxylate.

To a solution of 3 g. of methyl5-(1-acetoxyethyl)-7-methylxanthene-2-carboxylate in 80ml. of acetoneare added 12 ml. of 8 N chromic acid in 8N sulfuric acid. The resultantmixture is stirred at room temperature for 11/4 hours. Excess chromicoxide is decomposed with aqueous sodium bisulfite and to the resultantmixture are added 500 ml. of water. The resultant mixture is stripped ofsolvent and extracted with methylene chloride. The methylene chlorideextracts are washed with 10% aqueous sodium bicarbonate solution and thewashed extracts are concentrated in vacuum to give methyl5-(1-acetoxyethyl)-7-methylxanthone-2-carboxylate.

A solution of 2.70 g. of methyl5-(1-acetoxyethyl)-7-methylxanthone-2-carboxylate in 300 ml. of a 10%potassium hydroxide 10% aqueous methanol solution is heated under refluxunder a nitrogen atmosphere for a period of 1 hour. After this time, 40ml. of concentrated hydrochloric acid in 70 ml. of water are added.Thereafter, 100 ml. of water are added and the resultant solution isstripped of solvent in vacuum and filtered to give5-(1-hydroxyethyl)-7-methylxanthone-2-carboxylic acid.

In like manner, by subjecting the other 5-acyl xanthone-2-carboxyliccompounds of Example 15 to the procedure of the present example, thecorresponding products are prepared, e.g.:

5-(1-hydroxypropyl)-7-methylxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-ethylxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-ethylxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-n-propylxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-n-propylxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-isopropylxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-isopropylxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-n-octylxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-n-octylxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-methoxyxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-methoxyxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-ethoxyxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-ethoxyxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-n-propoxyxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-n-propoxyxanthone-2-carboxylic acid,

5-(1-hydroxyethyl)-7-isopropoxyxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-isopropoxyxanthone-2-carboxylic acid,

5-(hydroxyethyl)-7-n-octyloxyxanthone-2-carboxylic acid,

5-(1-hydroxypropyl)-7-n-octyloxyxanthone-2-carboxylic acid, and the5-(1-hydroxybutyl) compounds corresponding thereto, and so forth.

EXAMPLE 18

The procedure of Example 17 is repeated with the starting compounds ofExample 16 to prepare the following:

5-methyl-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-methyl-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-ethyl-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-ethyl-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-n-propyl-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-n-propyl-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-n-octyl-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-n-octyl-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-methoxy-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-methoxy-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-ethoxy-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-ethoxy-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-n-propoxy-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-n-propoxy-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-(1-hydroxyethyl)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-(1-hydroxypropyl)-xanthone-2-carboxylic acid, and the7-(1-hydroxybutyl) compounds corresponding thereto, and so forth.

EXAMPLE 19

A mixture of 3 g. of 5,7-dimercaptoxanthone-2-carboxylic acid in 150 ml.of dimethylformamide, 5ml. of methyl iodide and 5 ml. of potassiumcarbonate is stirred for 16 hours at 60° C. The mixture is then pouredinto dilute hydrochloric acid and the resultant mixture extracted withethyl acetate. The extracts are chromatographed on alumina (methylenechloride) to give methyl 5,7-di(methylthio)-xanthone-2-carboxylate (i.e.methyl 5,7-di(thiomethoxy)-xanthone-2-carboxylate) which can berecrystallized from methylene chloride/methanol.

A mixture of 580 mg. of methyl5,7-di(methylthio)-xanthone-2-carboxylate, 30 ml. of ethanol, 5 ml. ofsaturated sodium carbonate solution and 5 ml. of water is refluxed forone hour. The mixture is then cooled, acidified and the precipitatefiltered off to give 5,7-di(methylthio)-xanthone-2-carboxylic acid (i.e.5,7-di(thiomethoxy)-xanthone-2-carboxylic acid) as also prepared in thealternative method described in Example 1.

A mixture of 0.8 g. of 5,7-dimercaptoxanthone-2-carboxylic acid, 2 ml.of 2-bromopropane, and excess potassium carbonate in 50 ml. ofdimethylformamide is stirred for 24 hours at 75° C. Dilute hydrochloricacid and ethanol are added, the solid filtered off and washed. The solidis saponified with sodium carbonate in aqueous methanol (30 minutesreflux). The alkaline solution is diluted with water, treated withcharcoal, filtered, and acidified to give5,7-di(isopropylthio)-xanthone-2-carboxylic acid which can berecrystallized from tetrahydrofuran/ethyl acetate.

The foregoing are useful as an alternative to the method of Example 1for the preparation of the compounds thereof which are useful asdescribed in the above examples.

EXAMPLE 20

The compound 5,7-dimercaptoxanthone-2-carboxylic acid is treated by theprocedure of Example 15, paragraph 1, to prepare5,7-dimercaptoxanthone-2-carboxylic acid. This compound is treated inaccordance with the procedure of Example 6 to give5,7-di(chlorosulfonyl)-xanthone-2-carboxylic acid. This compound istreated in accordance with the procedure of Example 15, paragraph 4, togive 5,7-di(chlorosulfonyl)-xanthone-2-carboxylic acid, which is usefulas described in the above examples.

EXAMPLE 21

The compounds 5-alkyl(or 7-alkyl)-7-methoxy-(or5-methoxy)-xanthone-2-carboxylic acid are prepared as described inExample 1. Thereafter, these compounds are treated in accordance withthe procedure of Example 5, paragraph 2, to give 5-alkyl (or7-alkyl)-7-hydroxy(or 5-hydroxy)-xanthone-2-carboxylic acid compoundswhich are useful as described in the above examples, c.f. Example 5.

EXAMPLE 22

The procedures of Example 1 are repeated to prepare the 5,7-diloweralkoxyxanthone-2-carboxylic acid compounds hereof. Alternatively,5,7-dihydroxyxanthone-2-carboxylic acid is prepared as described inExample 5 and treated as follows:

5,7-Dihydroxyxanthone-2-carboxylic acid (1.3 g.) in 30 ml. ofdimethylformamide containing 5 g. of n-propylbromide and 5 g. ofpotassium carbonate is stirred at 60° C for 18 hours. The reactionmixture is then acidified and the acidified mixture partially evapoatedin vacuum to remove excess n-propylbromide. The mixture is then filteredand the filtered precipitate washed and then dissolved in 100 ml. ofethanol. Twenty milliliters of 2N sodium hydroxide is then added and theresultant mixture refluxed for 60 minutes. The mixture is then cooled,diluted with water, and filtered. The filtrate is acidified and theacidified mixture evaporated to give5,7-di(n-propoxy)-xanthone-2-carboxylic acid which is recrystallizedfrom ethanol-water.

In a similar manner, the following are prepared:

5,7-diethoxyxanthone-2-carboxylic acid,

5,7-diisopropoxyxanthone-2-carboxylic acid,

5,7-di-n-butoxyxanthone-2-carboxylic acid,

5,7-di-sec-butoxyxanthone-2-carboxylic acid,

5,7-diisobutoxyxanthone-2-carboxylic acid,

5,7-di-ti-butoxyxanthone-2-carboxylic acid,

5,7-dipentyloxyxanthone-2-carboxylic acid,

5,7-diisopentyloxyxanthone-2-carboxylic acid, and

5,7-dicyclopentyloxyxanthone-2-carboxylic acid.

EXAMPLE 23

The 5-lower alkyl(or 7-lower alkyl)-7-hydroxy(or5-hydroxy)-xanthone-2-carboxylic acid products of Example 21 aresubjected to the procedure of Example 22 to prepare the followingcompounds:

5-methyl-7-methoxyxanthone-2-carboxylic acid,

5-methyl-7-ethoxyxanthone-2-carboxylic acid,

5-methyl-7-n-propoxyxanthone-2-carboxylic acid,

5-methyl-7-isopropoxyxanthone-2-carboxylic acid,

5-methyl-7-n-butoxyxanthone-2-carboxylic acid,

5-methyl-7-isobutoxyxanthone-2-carboxylic acid,

5-methyl-7-sec-butoxyxanthone-2-carboxylic acid,

5-methyl-7-t-butoxyxanthone-2-carboxylic acid,

5-methyl-7-n-pentyloxyxanthone-2-carboxylic acid,

5-methyl-7-isopentyloxyxanthone-2-carboxylic acid,

5-methyl-7-cyclopentyloxyxanthone-2-carboxylic acid, and thecorresponding eleven 7-alkoxy compounds in each of the 5-ethyl,-n-propyl, -isopropyl, -n-butyl, -isobutyl, -sec-butyl, -t-butyl,-n-pentyl, -isopentyl, -cyclopentyl and the corresponding 121 compoundsin the 5-lower alkoxy-7-lower alkyl-xanthone-2-carboxylic acid series,e.g.:

5-methoxy-7-methylxanthone-2-carboxylic acid, and so forth.

EXAMPLE 24

A mixture of 51.5 g. of 1,3-dimethyl-4-iodobenzene (4-iodo-m-xylene), 40g. of o,p-dimethoxyphenol, 16 g. of cuprous oxide in 300 ml. ofdimethylacetamide is heated to the boiling point and maintained underreflux (190° C) for 144 hours with stirring and under a nitrogenatmosphere. The reaction mixture is then poured into ice water andextracted with ether and the extracts are filtered through 500 g. ofalumina in hexane to give1,3-dimethyl-4-(o,p-dimethoxyphenyloxy)-benzene.

A mixture of 41 g. of 1,3-dimethyl-4-(o,p-dimethoxy-phenyloxy)-benzene,300 g. of potassium permanganate, 500 ml. of t-butanol, and 750 ml. ofwater is heated to the boiling point and maintained thereat for a periodof 3 hours. After distilling off the t-butanol, the reaction mixture isfiltered, the clear filtrate acidified and the precipitate of1,3-di-carboxy-4-(o,p-dimethoxyphenyloxy)-benzene is isolated by suctionfiltration and washed with water.

The 1,3-dicarboxy-4-(o,p-dimethoxyphenyloxy)-benzene thus prepared isthen cyclized as described in Example 1 or 25 to give5,7-dimethoxyxanthone-2-carboxylic acid which can be converted to5,7-dihydroxyxanthone-2-carboxylic acid and/or thence to other compoundsas described above.

In a similar manner, the foregoing procedure can be practiced utilizingother o-, p-, or o,p-lower alkoxyphenol starting compounds to preparethe corresponding products, for example,

5,7-di(ethoxy)-xanthone-2-carboxylic acid,

5,7-di(n-propoxy)-xanthone-2-carboxylic acid,

5,7-di(isopropoxy)-xanthone-2-carboxylic acid,

5,7-di(n-butoxy)-xanthone-2-carboxylic acid, and so forth,

which can each be converted to other compounds hereof as describedabove.

EXAMPLE 25

A mixture of 1,3-dimethyl-4bromobenzene, 10,5 g. of o,p-dimethoxyphenol,4.65 g. of cuprous oxide, 40 ml. of tetramethylurea, and 75 ml. ofN-methylpyrrolidone is stirred at 165° for 96 hours. The resultantmixture is diluted with water and extracted with methylene chloride. Themethylene chloride extracts are chromatographed on 300 g. of aluminawith gradient elution using hexane:ether to give1,3-dimethyl-4-(o,p-di-methoxyphenyloxy)-benzene.

A mixture of 12 g. of 1,3-dimethyl-4-(o,p-dimethoxy-phenyloxy)-benzene,72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml. ofwater is refluxed for 41/2 hours. After this time, the t-butanol isdistilled off, and the reaction mixture is filtered. The filtrate isacidified to give 1,3-dicarboxy-4-(o,p-dimethoxyphenyloxy)-benzene whichcan be recrystallized from benzene:heptane.

A mixture of 3 g. of 1,3-dicarboxy-4-(o,p-dimethoxyphenyloxy)-benzene,75 ml. of polyphosphoric acid, and 75 ml. of sulfolane is stirred at125° C for a period of 2 hours. After this time, the reaction mixture ispoured into water, filtered and the precipitate washed. The precipitateis recrystallized from acetic acid (charcoal) to give5,7-di-methoxyxanthone-2-carboxylic acid which can be converted to5,7-dihydroxyxanthone-2-carboxylic acid and/or thence to other compoundsas described above.

EXAMPLE 26

A mixture of 2 g. of 5,7-di(1-hydroxyethyl)-xanthone-2-carboxylic acidin 20 ml. of pyridine and 10 ml. of acetyl chloride is heated at steambath temperatures for 1 hour. The mixture is then poured into HCl/icewater and the solid which forms is collected by filtration, washed withwater and dried to yield 5,7-di(1-acetoxyethyl)-xanthone-2-carboxylicacid.

Upon substitution of stoichiometrically appropriate amounts of theappropriate acyl chloride in the above procedure and, in addition,employing as starting compounds the products listed in Examples 10, 17and 18, the following compounds are prepared:

5,7-di(1-propionyloxyethyl)-xanthone-2-carboxylic acid,

5,7-di(1-butyryloxyethyl)-xanthone-2-carboxylic acid,

5,7-di(1-acetoxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-acetoxy-n-butyl)-xanthone-2-carboxylic acid,

5,7-di(1-acetoxy-isobutyl)-xanthone-2-carboxylic acid, and so forth,

5-(1-acetoxyethyl)-7-methylxanthone-2-carboxylic acid,

5-(1-acetoxyethyl)-7-isopropylxanthone-2-carboxylic acid,

5-(1-acetoxyethyl)-7-n-octylxanthone-2-carboxylic acid,

5-(1-acetoxyethyl)-7-methoxyxanthone-2-carboxylic acid,

5-(1-acetoxyethyl)-7-isopropoxyxanthone-2-carboxylic acid,

5-(1-acetoxyethyl)-7-n-octyloxyxanthone-2-carboxylic acid, and so forth,

5-methyl-7-(1-acetoxyethyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-acetoxyethyl)-xanthone-2-carboxylic acid,

5-n-octyl-7(1-acetoxyethyl)-xanthone-2-carboxylic acid,

5-methoxy-7-(1-acetoxyethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1 -acetoxyethyl)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-(1-acetoxyethyl)-xanthone-2-carboxylic acid, and soforth,

5,7-di((cyclopropyl)acetoxymethyl)-xanthone-2-carboxylic acid,

5,7-di(1-propionyloxyisobutyl)-xanthone-2-carboxylic acid,

5-methyl-7-((phenyl)acetoxymethyl)-xanthone-2-carboxylic acid, and

5-(1-acetoxyisobutyl)-7-isopropoxyxanthone-2-carboxylic acid.

EXAMPLE 27

Methyl 5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate is prepared fromthe acid by the method of Example 2. To a mixture of 2.5 g. of methyl5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate and 1 g. of sodium hydridein 100 ml. of dimethyl-formamide is added 5 ml. of methyl iodide and themixture is stirred at room temperature for 16 hours. The mixture is thenpoured into dilute HCl/ice water, filtered and dried to give methyl5,7-di(1-methoxyethyl)-xanthone-2-carboxylate.

The resultant product is hydrolyzed according to the procedure ofParagraph (B) of Example 1 to give5,7-di(1-methoxy-ethyl)-xanthone-2-carboxylic acid.

Upon substitution of stoichiometrically appropriate amounts of theappropriate alkyl or cycloalkyl iodide or bromide and, in addition,employing as starting compounds the products listed in Examples 10, 17and 18, the following compounds are prepared, through their respectiveesters:

5,7-di(1-ethoxyethyl)-xanthone-2-carboxylic acid,

5,7-di(1-methoxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-ethoxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-methoxyisobutyl)-xanthone-2-carboxylic acid,

5,7-di(1-isopropoxyethyl)-xanthone-2-carboxylic acid,

5,7-di(1-isopropoxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-isopropoxyisobutyl)-xanthone-2-carboxylic acid,

5,7-di(1-cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

5,7-di(1-cyclopentyloxy-n-propyl)-xanthone-2-carboxylic acid,

5-methyl-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-methoxy-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-n-octyl-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-(1-methoxyethyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-ethoxyethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1-ethoxyethyl)-xanthone-2-carboxylic acid,

5-(1-methoxyethyl)-7-methylxanthone-2-carboxylic acid,

5-(1-methoxyethylL)-7-methoxyxanthone-2-carboxylic acid,

5-(1-methoxyethyl)-7-isopropylxanthone-2-carboxylic acid,

5-(1-methoxyethyl)-7-isopropoxyxanthone-2-carboxylic acid,

5-(1-ethoxyethyl)-7-isopropylxanthone-2-carboxylic acid,

5-(1-ethoxyethyl)-7-isopropoxyxanthone-2-carboxylic acid,

5-methoxy-7-(1-methoxy-n-butyl)-xanthone-2-carboxylic acid,

5-(1-methoxy-n-butyl)-7-methoxyxanthone-2-carboxylic acid,

5-isobutyl-7-(1-ethoxyisobutyl)-xanthone-2-carboxylic acid,

5-(1-methoxyisobutyl)-7-isopropylxanthone-2-carboxylic acid,

5,7-di((cyclopropyl)methoxymethyl)-xanthone-2-carboxylic acid,

5-((cyclopropyl)methoxymethyl)-7-cyclopropylxanthone-2-carboxylic acid,

5,7-di((phenyl)methoxymethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-((phenyl)methoxymethyl)-xanthone-2-carboxylic acid,

5-n-octyloxy-7-((phenyl)methoxymethyl)-xanthone-2-carboxylic acid,

5,7-di(1-propoxyethyl)-xanthone-2-carboxylic acid, and

5-(1-isopropoxyethyl)-7-methylxanthone-2-carboxylic acid.

EXAMPLE 28

A mixture of 1.6 g. of methyl5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate, 100 ml. of methylenechloride, 100 ml. of isobutene and 2 ml. of BF₃ /H₂ PO₄ catalyst areshaken in a pressure bottle for 4 days at room temperature. The reactionmixture is diluted with methylene chloride, washed with bicarbonatesolution, then water, dried and evaporated and crystallized frommethanol to give methyl 5,7-di(1-t-butoxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides 5,7-di(1-t-butoxyethyl)-xanthone-2-carboxylic acid.

Likewise, the following products are prepared from the respectivestarting compounds:

5,7-di(1-t-butoxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-t-butoxyisobutyl)-xanthone-2-carboxylic acid,

5,7-di(1-t-butoxy-n-propyl)-xanthone-2-carboxylic acid,

5-(1-t-butoxyethyl)-7-methoxyxanthone-2-carboxylic acid,

5-(1-t-butoxyethyl)-7-isopropoxyxanthone-2-carboxylic acid,

5,7-di((cyclopropyl)-t-butoxymethyl)-xanthone-2-carboxylic acid,

5-((cyclopropyl)-t-butoxymethyl)-7-isopropylxanthone-2-carboxylic acid,

5,7-di((phenyl)-t-butoxymethyl)-xanthone-2-carboxylic acid,

5-methyl-7-((phenyl)-t-butoxymethyl)-xanthone-2-carboxylic acid,

5-isopropyl-7-(1-t-butoxyethyl)-xanthone-2-carboxylic acid,

5-isopropoxy-7-(1-t-butoxyethyl)-xanthone-2-carboxylic acid, and

5-n-octyloxy-7-(1-t-butoxyethyl)-xanthone-2-carboxylic acid.

EXAMPLE 29

Twenty milliliters of dihydropyran are added to a solution of 1 g. ofmethyl 5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate in 100 ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.8 g. of p-toluenesulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is crystallized fromchloroform/methanol/pyridine to yield methyl5,7-di(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides5,7-di(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylic acid.

By use of dihydrofuran in the above procedure,5,7-di-(1-tetrahydrofuran-2'-yloxyethyl)-xanthone-2-carboxylic acid isprepared.

In like manner, the following compounds are prepared:

5-methyl-7-(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylic acid,

5-methoxy-7-(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylicacid,

5-isopropyl-7-(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylicacid,

5-isopropoxy-7-(1-tetrahydropyran-2'-yloxyethyll)-xanthone-2-carboxylicacid,

5-n-octyloxy-7-(1-tetrahydropyran-2'-yloxyethyl)-xanthone-2-carboxylicacid, and the tetrahydrofuran-2-yloxy compounds corresponding thereto,

5-(1-tetrahydropyran-2'-yloxyethyl)-7-methylxanthone-2-carboxylic acid,

5-(1-tetrahydropyran-2'-yloxyethyl)-7-methoxyxanthone-2-carboxylic acid,

5-(1-tetrahydropyran-2'-yloxyethyl)-7-isopropylxanthone-2-carboxylicacid,

5-(1-tetrahydropyran-2'-yloxyethyl)-7-isopropoxyxanthone-2-carboxylicacid,

5-(1-tetrahydropyran-2'-yloxyethyl)-7-n-octyloxyxanthone-2-carboxylicacid, and the tetrahydrofuran-2'-yloxy compounds corresponding thereto,

5,7-di(1-tetrahydropyran-2'-yloxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-tetrahydropyran-2'-yloxy-isobutyl)-xanthone-2-carboxylic acid,and

5,7-di(1-tetrahydrofuran-2'-yloxy-n-propyl)-xanthone-2-carboxylic acid.

3.5 Grams of methyl 5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate in 150ml. of benzene and 1 g. of p-toluenesulfonic acid (dried by azeotropicdistillation from benzene) are mixed together and the reaction mixtureis treated with 4-methoxy-5,6-dihydro-2H-pyran, 1 ml. at a time untilreaction is complete (followed by tlc). The reaction is quenched byaddition of one-half ml. of triethylamine, washed with water, andcrystallized with care from methanol containing pyridine to give methyl5,7-di(1-4'-methoxytetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides5,7-di(1-4'-methoxytetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid.

A solution of 3.0 g. of aluminum chloride in 50 ml. of tetrahydrofuranis treated with a solution of 0.8 g. of lithium aluminum hydride in 100ml. of tetrahydrofuran. Methyl5,7-di(1-4'-methoxytetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylate(500 mg.) is extracted into the solution. After reduction is complete(monitored by tlc), saturated sodium chloride is added until aprecipitate forms. This is filtered and the crude product is oxidized inacetic using excess sodium dichromate to give5,7-(1-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylic acid.

In like manner, the following compounds are prepared:

5,7-di(1-4'-methoxytetrahydropyran-4'-yloxy-n-propyl)-xanthone-2-carboxylicacid,

5,7-di(1-tetrahydropyran-4'-yloxy-n-propyl)-xanthone-2-carboxylic acid,

5,7-di(1-4'-ethoxytetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid,

5,7-di(1-4'-methoxytetrahydropyran-4'-yloxyisobutyl)-xanthone-2-carboxylicacid,

5-isopropyl-7-(1-4'-methoxytetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid,

5-isopropoxy-7-(1-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid,

5-(1-tetrahydropyran-4'-yloxyethyl)-7-isopropyl-xanthone-2-carboxylicacid,

5-(1-tetrahydropyran-4'-yloxyethyl)-7-isopropoxy-xanthone-2-carboxylicacid,

5-(1-4'-propoxytetrahydropyran-4'-yloxy-n-propyl)-7-methylxanthone-2-carboxylicacid, and

5-methoxy-7-(1-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid, and

5-n-octyloxy-7-(1-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylicacid.

EXAMPLE 30

A mixture of 4.5 g. of 5,7-di(methylsulfinyl)-xanthone-2-carboxylicacid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in 75 ml.of dimethylformamide is stirred at room temperature for a period of 18hours. After this period of time, the reactin mixture is poured intodilute hydrochloric acid-ice and the resultant precipitate is filteredoff and washed to give methyl5,7-di(methylsulfinyl)-xanthone-2-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyliodides so as to prepare the corresponding lower alkyl acid estershereof, e.g.:

ethyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

n-propyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

isopropyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

n-propyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

isobutyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

sec-butyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

n-pentyl 5,7-di(methylsulfinyl)-xanthone-2-carboxylate, and so forth.

In like manner, the other xanthone-2-carboxylic acids hereof containingsubstituents at the C-5,7 positions, prepared as described above, can beconverted to the corresponding acid esters, e.g.:

methyl 5,7-di(methylsulfonyl)-xanthone-2-carboxylate,

ethyl 5-methylsulfonyl-7-isopropoxyxanthone-2-carboxylate,

n-propyl 5,7-disulfamoylxanthone-2-carboxylate,

methyl 5-acetyl-7-ethylxanthone-2-carboxylate, and so forth.

In the sulfo series, the esters are prepared by treating the acid withthe appropriate lower alkanol under reflux and in the absence of acid togive, e.g.:

methyl 5,7-disulfoxanthone-2-carboxylate, and

ethyl 5,7-disulfoxanthone-2-carboxylate.

EXAMPLE 31

To a solution of 10 g. of 5,7-di(methylsulfinyl)-xanthone-2-carboxylicacid in 200 ml. of ethanol is added the theoretical amount of sodiumhydroxide dissolved in 200 ml. of 90% ethanol. The reaction mixture isthen concentrated in vacuum to give sodium5,7-di(methylsulfinyl)-xanthone-2-carboxylate.

In a similar manner, the potassium and lithium salts are prepared.Similarly, by replacing the sodium salt by means of an appropriate metalsalt reagent, e.g. calcium chloride, manganese chloride, and so forth,the other xanthone-2-carboxylic acid salts are prepared, e.g.:

magnesium 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

calcium 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

aluminum 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

ferrous 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

zinc 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

manganese 5,7-di(methylsulfinyl)-xanthone-2-carboxylate,

ferric 5,7-di(methylsulfinyl)-xanthone-2-carboxylate, and so forth.

In a similar manner, the xanthone-2-carboxylic acid salts of the otherC-5,7 disubstituted xanthone-2-carboxylic acids hereof are prepared,e.g.:

potassium 5,7-di(methylsulfonyl)-xanthone-2-carboxylate,

sodium 5-isopropyl-7-methylsulfinylxanthone-2-carboxylate,

potassium 5,7-di(1-hydroxyethyl)-xanthone-2-carboxylate,

sodium 5,7-sulfamoylxanthone-2-carboxylate,

sodium 5-isopropoxy-7-methylsulfinylxanthone-2-carboxylate,

sodium 5-isopropoxy-7-acetylxanthone-2-carboxylate,

sodium 5-methylsulfonyl-7-isopropoxyxanthone-2-carboxylate,

sodium 5-methylsulfinyl-7-isopropoxyxanthone-2-carboxylate,

sodium 5-butoxy-7-methylsulfonylxanthone-2-carboxylate,

sodium 5-acetyl-7-isopropoxyxanthone-2-carboxylate,

sodium 5-cyclopentyloxy-7-methylsulfinylxanthone-2-carboxylate,

sodium 5-n-pentyloxy-7-methylsulfinylxanthone-2-carboxylate,

sodium 5-isopentyloxy-7-methylsulfinylxanthone-2-carboxylate,

sodium 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, and soforth.

In the sulfo series, use of one equivalent of base provides the sulfoacid salt and use of two or more equivalents provides the disalt, e.g.5,7-disulfoxanthone-2-carboxylic acid disodium salt.

EXAMPLE 32

To a mixture of 50 ml. of concentrated aqueous ammonia in 500 ml. ofmethanol there are added 20 g. of 5,7-disulfamoylxanthone-2-carboxylicacid. The resultant mixture is stirred for two hours and is thenevaporated to dryness to give the ammonium salt of5,7-disulfamoylxanthone-2-carboxylic acid.

A solution of 10 g. of 5,7-disulfamoylxanthone-2-carboxylic acid in 50ml. of thionyl chloride is heated at reflux for one hour. Thereafter,the solution is evaporated to dryness to give the corresponding acidchloride to which is added a concentrated ethereal ammonia solution. Theresultant solution is evaporated giving the5,7-disulfamoylxanthone-2-carboxylic acid amide.

In like manner, the lower alkyl amides can be prepared usingmonoalkylamine or dialkylamine in lieu of ammonia in the aboveprocedures. Thus prepared, are, e.g.:

5,7-di(methylsulfamoyl)-xanthone-2-carboxylic acid amide,

N-methyl 5,7-di(n-propylsulfinyl)-xanthone-2-carboxylic acid amide,

N,n-dimethyl 5-(dimethylsulfamoyl)-7-methylxanthone-2-carboxylic acidamide,

N,n-diethyl 5,7-di(ethylsulfonyl)-xanthone-2-carboxylic acid amide,

N,n-diethyl 5,7-diacetylxanthone-2-carboxylic acid amide,

N-ethyl 5-ethoxy-7-sulfoxanthone-2-carboxylic acid amide,

N-n-propyl 5-propyl-7-(propylsulfinyl)-xanthone-2-carboxylic acid amide,and so forth.

EXAMPLE 33

To a mixture of 20 g. of procaine and 500 ml. of aqueous methanol areadded 20 g. of 5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid. Theresultant mixture is stirred at room temperature for 16 hours. It isthen evaporated under reduced pressure, to give the procaine salt of5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid.

Similarly, the lysine, caffeine, and arginine salts thereof areobtained. In like manner, the e.g. procaine, lysine, caffeine, andarginine salts of the other C-5,7 disubstituted xanthone-2-carboxylicacids are obtained, e.g.:

the procaine salt of 5,7-di(ethylsulfonyl)-xanthone-2-carboxylic acid,

the caffeine salt of 5-(propylsulfinyl)-7-n-butoxyxanthone-2-carboxylicacid,

the lysine salt of 5,7-di(di-t-butylsulfamoyl)-xanthone-2-carboxylicacid,

the procaine salt of5-(sec-butylsulfinyl)-7-sec-butoxyxanthone-2-carboxylic acid, and

the arginine salt of 5,7-disulfoxanthone-2-carboxylic acid.

EXAMPLE 34

The following procedures illustrate the method by which thepharmaceutical compositions of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in 80 ml. of a (9.47 g/l. water)sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00g/l. water) solution (20 ml.) is then added thereto. The resultantsolution having a pH of 7.38 is sterilized in an autoclave. This vehicleis then added to solid, dry 5,7-di(methylsulfinyl)-xanthone-2-carboxylicacid to give a preparation suitable for intravenous injection containing2.5 mg. of 5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid per ml. oftotal composition.

EXAMPLE 35

The following procedure illustrates a test procedure for the compoundshereof.

Normal female (Sprague-Dawley) rats of 150 to 200 grams each arepassively sensitized intradermally by injection of rat anti-egg albuminreaginic sera. After 24 hours, each rat is challenged intravenously with1 ml. of 0.5% Evans blue, 1 mg. egg albumin plus 10 mg. of5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid. Control rats receiveno 5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid. The dermal bluingis recorded 15 to 25 minutes later. The rats which receive the5,7-di(methylsulfinyl)-xanthone-2-carboxylic acid exhibit a 100%inhibition of allergic reaction whereas the control rats exhibit noinhibition.

The above procedure is repeated using5,7-di(methylsulfonyl)-xanthone-2-carboxylic acid, with similar results.The above procedure is repeated using oral administration, with similarresults.

The C-5,7 disubstituted xanthone-2-carboxylic acid compounds areadministered by gavage at a dose of 20 mg. per animal 15 minutes priorto challenge. Twenty to thirty minutes after challenge the degree ofdermal bluing is read, with similar results.

Inhibition of reaginic antigen-antibody reactions in rats is regarded asrepresentative of inhibition of human reaginic antigen-antibodyreactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent ofprovoked degree of asthma condition by changes in airway resistance onexpiration. The subject compounds are administered as an aerosol byinhalation before antigen challenge. Prevention of asthmatic conditionsupon the administration of the compounds is evidenced by a decrease inairway resistance and other, subjective improvements, e.g. reducedcough.

EXAMPLE 36

A. To a suspension of 14.5 g.5-methoxy-7-(methylthio)-xanthone-2-carboxylic acid in 350 ml. of aceticanhydride, 100 ml. 47% hydriodic acid is added dropwise with icecooling. After refluxing the resulting mixture for 20 hours, it isdiluted with 750 ml. of hot water and cooled. The yellow product isfiltered off, washed with water and dried to give 12.8 g.5-hydroxy-7-(methylthio)-xanthone-2-carboxylic acid.

Similarly, substituting 5-methylthio-7-methoxyxanthone-2-carboxylic acidfor 5-methoxy-7-(methylthio)-xanthone-2-carboxylic acid yields5-methylthio-7-hydroxyxanthone-2-carboxylic acid.

In like manner, other 5-hydroxy-7-(loweralkylthio)-xanthone-2-carboxylic acids and 5-loweralkylthio-7-hydroxyxanthone-2-carboxylic acids are obtained.

B. A mixture of 6.65 g. of5-hydroxy-7-(methylthio)-xanthone-2-carboxylic acid, 4.5 g. of drylithium carbonate, 4 ml. of methyl iodide and 70 ml. ofdimethylformamide is stirred at room temperature for 20 hours. Afteradding an excess of acetic acid/water (1:1), excess methyl iodide isremoved on a rotary evaporator. The crystalline product is filtered off,washed and dried to give 6.8 g. of methyl5-hydroxy-7-(methylthio)-xanthone-2-carboxylate.

Similarly, substituting 5-methylthio-7-hydroxyxanthone-2-carboxylic acidin the foregoing procedure yields methyl5-methylthio-7-hydroxyxanthone-2-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyliodides so as to prepare the lower alkyl acid esters hereof, e.g., ethyl5-hydroxy-7-(methylthio)-xanthone-2-carboxylate, pentyl5-hydroxy-7-(methylthio)-xanthone-2-carboxylate, and ethyl5-methylthio-7-hydroxyxanthone-2-carboxylate, andpentyl-5-methylthio-7-hydroxyxanthone-2-carboxylate.

C. 1.55 g. of methyl 5-hydroxy-7-(methylthio)-xanthone-2-carboxylate isstirred at room temperature with 2.5 g. of octyl bromide and 1.0 g. ofpotassium carbonate in 30 ml. of dimethylformamide for 18 hours. Afteracidification with dilute hydrochloric acid, the mixture is extractedwith chloroform, the extracts washed with water, dried over magnesiumsulfate, and evaporated. Filtration of a chloroform solution of thecrude product through alumina (activity II) afforded 2.0 g. of methyl5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate.

Similarly, substituting methyl5-methylthio-7-hydroxyxanthone-2-carboxylate in the foregoing procedureyields methyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate.

The foregoing procedure is repeated using other higher alkyl bromides soas to prepare the 5- and 7-higher alkoxy compounds e.g.,

methyl 5-n-hexyloxy-7-(methylthio)-xanthone-2-carboxylate,

methyl 5-n-heptyloxy-7-(methylthio)-xanthone-2-carboxylate,

methyl 5-n-dodecyloxy-7-(methylthio)-xanthone-2-carboxylate, and

methyl 5-methylthio-7-n-hexyloxyxanthone-2-carboxylate,

methyl 5-methylthio-7-n-heptyloxyxanthone-2-carboxylate, and

methyl 5-methylthio-7-n-dodecyloxyxanthone-2-carboxylate.

In like manner, other lower alkyl esters may be substituted for themethyl ester, and with the use of the appropriate higher alkyl bromide,there is obtained, for example,

ethyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate,

pentyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate,

ethyl 5-n-hexyloxy-7-(methylthio)-xanthone-2-carboxylate,

pentyl 5-n-heptyloxy-7-(methylthio)-xanthone-2-carboxylate,

ethyl 5-n-dodecyloxy-7-(methylthio)-xanthone-2-carboxylate,

ethyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate,

pentyl 5-methylthio-7-n-octyloxyxanthone-2-carboxylate,

ethyl 5-methylthio-7-n-hexyloxyxanthone-2-carboxylate,

pentyl 5-methylthio-7-n-hexyloxyxanthone-2-carboxylate, and

ethyl 5-methylthio-7-n-dodecyloxyxanthone-2-carboxylate.

D. To 2.0 g. of methyl5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate in 60 ml. ofchloroform there is slowly added a solution of 910 mg. ofm-chloroperoxybenzoic acid in 40 ml. of chloroform while keeping thetemperature at about 0° C. After the addition is complete, the solutionis filtered through alumina (activity III) and evaporated to give 2.0 g.of methyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate.

Similarly, substituting methyl5-methylthio-7-n-octyloxyxanthone-2-carboxylate in the foregoingprocedure yields methyl5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate.

Likewise, substituting the other compounds prepared in Part (C) of thisexample for 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate, isproductive of, for example,

methyl 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate,

methyl 5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylate,

methyl 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate,

ethyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate,

pentyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate,

ethyl 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate,

pentyl 5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylate, and

ethyl 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, and

methyl 5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylate,

methyl 5-methylsulfinyl-7-n-heptyloxyxanthone-2-carboxylate,

methyl 5-methylsulfinyl-7-n-dodecyloxyxanthone-2-carboxylate,

ethyl 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate,

pentyl 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate,

ethyl 5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylate,

pentyl 5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylate and

ethyl 5-methylsulfinyl-7-n-dodecyloxyxanthone-2-carboxylate.

E. Methyl 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate (750 mg.),2 ml. of hydrogen peroxide (30%), and 40 ml. of acetic acid are heatedon a steam bath (80° C) for 90 minutes. Tlc indicates the absence ofstarting material. The mixture is diluted with 60 ml. of hot water, andthe mixture is cooled, the solid is filtered off and dried to givemethyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate which can berecrystallized from acetic acid/water.

Similarly, substituting methyl 5-methylthio-7-n-octyloxy-2-carboxylatein the foregoing procedure yields methyl5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate.

Likewise, substituting the other compounds prepared in Part (C) of thisexample for 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylate, isproductive of, for example,

methyl 5-n-hexyloxy-7-methylsulfonylxanthone-2-carboxylate,

methyl 5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylate,

methyl 5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate,

ethyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate,

pentyl 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate,

ethyl 5-n-hexyloxy-7-methylsulfonylxanthone-2-carboxylate,

pentyl 5-n-heptyloxy-methylsulfonylxanthone-2-carboxylate, and

ethyl 5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylate, and

methyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate,

methyl 5-methylsulfonyl-7-n-heptyloxyxanthone-2-carboxylate,

methyl 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate,

ethyl 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate,

pentyl 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylate,

ethyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate,

pentyl 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylate, and

ethyl 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylate.

F. 2.0 G. of methyl 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylateis refluxed for 30 minutes with 0.5 g. of potassium hydroxide in 80 ml.ethanol containing 20 ml. water. After acidifying with dilutehydrochloric acid, the precipitate is isolated by suction filtration andrecrystallized from tetrahydrofuran/ethanol to give 1.8 g.5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid.

Likewise, substituting as starting material the other compounds obtainedin Parts (D) and (E) of this example for methyl5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, there is obtained,for example,

5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-heptyloxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylic acid,

5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylic acid,

5-methylsulfinyl-7-n-heptyloxyxanthone-2-carboxylic acid, and

5-methylsulfinyl-7-n-dodecyloxyxanthone-2-carboxylic acid,

5-n-hexyloxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-heptyloxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylic acid,

5-methylsulfonyl-7-n-heptyloxyxanthone-2-carboxylic acid, and

5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid.

What is claimed is:
 1. The compound5-hydroxy-7-(methylthio)-xanthone-2-carboxylic acid.
 2. The compound5-methylthio-7-hydroxyxanthone-2-carboxylic acid.